Study characteristics

Methods

Study design: Randomised controlled trial

Study grouping: Parallel group

Methods: 5‐week dietary run‐in period; 12‐week randomised, double‐blind, placebo‐controlled trial

Participants

Baseline Characteristics

1 mg

• N: 26

• Age, years: 10.5

• Male sex, n: 12

• Female sex, n: 14

• Genetic FH diagnosis, n: 26

• Total cholesterol: 300.6 mg/dL (7.77 mmol/L)

• LDL cholesterol: 231.4 mg/dL (5.98 mmol/L)

2 mg

• N: 27

• Age, years: 11.1

• Male sex, n: 10

• Female sex, n: 17

• Genetic FH diagnosis, n: 26

• Total cholesterol: 295.0 mg/dL (7.63 mmol/L)

• LDL cholesterol: 223.1 mg/dL (5.77 mmol/L)

4 mg

• N: 26

• Age, years: 10.3

• Male sex, n: 14

• Female sex, n: 12

• Genetic FH diagnosis, n: 25

• Total cholesterol: 307.2 mg/dL (7.94 mmol/L)

• LDL cholesterol: 240.7 mg/dL (6.22 mmol/L)

Placebo

• N: 27

• Age, years: 10.4

• Male sex, n: 12

• Female sex, n: 15

• Genetic FH diagnosis, n: 26

• Total cholesterol: 310.1 mg/dL (8.02 mmol/L)

• LDL cholesterol: 240.5 mg/dL (6.22 mmol/L)

Overall

• N: 106

• Age, years: 10.6

• Male sex, n: 48

• Female sex, n: 58

• Genetic FH diagnosis, n: 103

Included criteria: Children, aged 6‐17 years were eligible if they had diet‐controlled fasting LDL‐C ≥ 160 (4.1 mmol/L) mg/dL,or LDL‐C ≥ 130 mg/dL (3.4 mmol/L) with one of the following risk factors: male; family history of premature cardiovascular disease; presence of low high‐density lipoprotein cholesterol (HDL‐C) 45 mg/dL or high triglycerides > 150 mg/dL; increased lipoprotein(a) > 75 nmol/L; type 2 diabetes mellitus diagnosed by treating physician according to current guidance; or systolic and diastolic blood pressures above the 95th percentile for age and height. Originally, children with an LDL‐C > 190 mg/dL without a risk factor and > 160 mg/dL with a risk factor could be enroled. These levels were changed to > 160 mg/dL without a risk factor and > 130 mg/dL with a risk factor

Excluded criteria: None

Baseline Group Characteristics: In general, the treatment groups were comparable with respect to all demographic and clinical characteristics

Interventions

Intervention Characteristics

1 mg

2 mg

4 mg

Placebo

Outcomes

Total cholesterol

• Outcome type: Continuous

• Reporting: Fully reported

• Unit of measure: Percentage change from baseline

• Direction: Lower is better

• Data value: Change from baseline

LDL‐cholesterol

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Lower is better

WDAE

• Outcome type: Dichotomous

• Reporting: Fully reported

• Unit of measure: Risk ratio

• Direction: Lower is better

Notes

Stephen P on 01/02/2018 10:33
Outcomes
Given versus calculated percentage changes from baseline for HDL cholesterol for each dose had a greater than 10% difference (placebo 1.1 vs ‐0.8), (1 mg/day 6.1 vs 4.9), (2 mg/day 2.4 vs ‐3.5) and (4 mg/day 3.1 vs ‐4.2) and triglycerides were expressed as medians; therefore, HDL cholesterol and triglyceride outcomes could not be reported
 

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Judgement Comment: method of sequence generation not reported

Allocation concealment (selection bias)

Unclear risk

Judgement Comment: method of allocation concealment not reported

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Judgement Comment: double‐blind placebo‐controlled trial

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Judgement Comment: Lipid parameters were measured in a remote laboratory.

Selective reporting (reporting bias)

Low risk

Judgement Comment: LDL‐C outcome was reported.

Other bias

High risk

Judgement Comment: Kowa Research Europe Ltd. supported the trial.

Incomplete outcome data (attrition bias) Total cholesterol

Low risk

All placebo and pitavastatin 1 mg/day participants were included in the efficacy analysis, [(27 ‐ 26)/27]*100 = 3.7%, pitavastatin 2 mg/day participants were not included in the efficacy analysis and [(26 ‐ 24)/26]*100 = 7.7% pitavastatin 4 mg/day participants were not included in the efficacy analysis.

Incomplete outcome data (attrition bias) LDL cholesterol)

Low risk

All placebo and pitavastatin 1 mg/day participants were included in the efficacy analysis, [(27 ‐ 26)/27]*100 = 3.7%, pitavastatin 2 mg/day participants were not included in the efficacy analysis and [(26 ‐ 24)/26]*100 = 7.7% pitavastatin 4 mg/day participants were not included in the efficacy analysis.

Incomplete outcome data (attrition bias) HDL cholesterol

High risk

Given versus calculated percentage changes from baseline for HDL cholesterol for each dose had a greater than 10% difference; HDL cholesterol was not included in the analysis

Incomplete outcome data (attrition bias) Triglycerides

High risk

Triglycerides were expressed as medians, therefore triglycerides were not included in the analysis.

Blinding of outcome assessment (detection bias)WDAEs

Unclear risk

Blinding method was not described.

Selective reporting (reporting bias) for WDAEs

Low risk

WDAE outcome reported

Study characteristics

Methods

Study design: Historically controlled trial

Study grouping: Parallel group

Methods: 6 to 8‐week dietary lead‐in period; 12‐week before‐and‐after trial

Participants

Baseline Characteristics

2 mg

• n: 316

• Age (years): 58.4

• Male: 142

• Female: 174

• Familial hypercholesterolaemia: 1

• Total cholesterol: 263.5 mg/dL (6.81mmol/L)

• LDL cholesterol: 183.5 mg/dL (4.75 mmol/L)

• HDL cholesterol: 48.5 mg/dL (1.25 mmol/L)

• Triglycerides: 157.7 mg/dL (1.78 mmol/L)

2 mg then uptitrated to 4 mg at week 4

• n: 300

• Age (years): 57.9

• Male: 136

• Female: 164

• Familial hypercholesterolaemia: 2

• Total cholesterol: 263.3 mg/dL (6.81 mmol/L)

• LDL cholesterol: 181.8 mg/dL (4.70 mmol/L)

• HDL cholesterol: 49.9 mg/dL (1.29 mmol/L)

• Triglycerides: 157.4 mg/dL (1.78 mmol/L)

2 mg combined data

• n: 616

• Age (years):

• Male: 278

• Female: 338

• Familial hypercholesterolaemia: 3

Overall

• n: 616

Included criteria: men and non‐pregnant, nonlactating women, aged 18 to 75 years, diagnosed with primary hypercholesterolaemia or combined dyslipidaemia. mean fasting LDL‐C levels of 160 mg/dL or more (4.1 mmol/L) and less than or equal to 220 mg/dL (5.7mmol/L), and TG levels of less than or equal to 400 mg/dL (4.5 mmol/L) at the end of the lead‐in period

Excluded criteria: previous contraindications or intolerance to statin therapy, homozygous familial hypercholesterolaemia, familial hypoalpha‐lipoproteinaemia, conditions that might have caused secondary dyslipidaemia, uncontrolled diabetes mellitus, pregnancy, conditions affecting absorption, distribution, metabolism or excretion of drugs, symptomatic heart failure (New York Heart Association classification III or IV), significant cardiovascular disease, impaired pancreatic function, liver enzyme levels greater than 1.5‐times the upper limit of normal, impaired renal function, impaired urinary tract function, uncontrolled hypothyroidism, symptomatic cerebrovascular disease, left ventricular ejection fraction less than 0.25, uncontrolled hypertension, muscular or neuromuscular disease, neoplastic disease, treatment with other lipid‐lowering drugs and treatment that would interact with the pharmacokinetics of statins. Women of childbearing potential were only allowed to participate if they were using a reliable contraceptive method.

Baseline Group Characteristics: The treatment groups were well matched in terms of age, vital statistics (height, weight and BMI) and disease diagnosis and duration. Approximately 79% of patients in each treatment group had primary hypercholesterolaemia (78.4 to 79.1%) and most of the remainder had combined dyslipidaemia. The groups were also well matched in diagnosis of hypertension and in baseline lipid values. Study subjects included slightly more women than men, and this balance was reflected across the treatment groups

Interventions

Intervention Characteristics

2 mg

2 mg then uptitrated to 4 mg at week 4

2 mg combined data

Outcomes

Total cholesterol

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Lower is better

LDL cholesterol

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Lower is better

HDL cholesterol

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Lower is better

Triglycerides

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Lower is better

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

Judgement Comment: Controlled before‐and‐after design

Allocation concealment (selection bias)

High risk

Judgement Comment: Controlled before‐and‐after design

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Judgement Comment: Lipid parameter measurements unlikely to be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Judgement Comment: Lipid parameters were measured in a remote laboratory.

Selective reporting (reporting bias)

Low risk

Judgement Comment: LDL‐cholesterol outcome was reported.

Other bias

High risk

Judgement Comment: Kowa Research Europe Ltd. sponsored the trial.

Incomplete outcome data (attrition bias) Total cholesterol

Low risk

[(316 ‐ 315)/316]*100 = 0.3% were not included in the efficacy analysis for the pitavastatin 2 mg/day; [(300 ‐ 298)/300]*100 = 0.7% were not included in the efficacy analysis for the pitavastatin 2 mg/day then titrated to 4 mg/day at week 4.

Incomplete outcome data (attrition bias) LDL cholesterol)

Low risk

[(316 ‐ 315)/316]*100 = 0.3% were not included in the efficacy analysis for the pitavastatin 2 mg/day; [(300 ‐ 298)/300]*100 = 0.7% were not included in the efficacy analysis for the pitavastatin 2 mg/day then titrated to 4 mg/day at week 4.

Incomplete outcome data (attrition bias) HDL cholesterol

Low risk

[(316 ‐ 315)/316]*100 = 0.3% were not included in the efficacy analysis for the pitavastatin 2 mg/day; [(300 ‐ 298)/300]*100 = 0.7% were not included in the efficacy analysis for the pitavastatin 2 mg/day then titrated to 4 mg/day at week 4.

Incomplete outcome data (attrition bias) Triglycerides

Low risk

[(316 ‐ 315)/316]*100 = 0.3% were not included in the efficacy analysis for the pitavastatin 2 mg/day; [(300 ‐ 298)/300]*100 = 0.7% were not included in the efficacy analysis for the pitavastatin 2 mg/day then titrated to 4 mg/day at week 4.

Blinding of outcome assessment (detection bias)WDAEs

High risk

No comparison possible

Selective reporting (reporting bias) for WDAEs

High risk

No WDAE outcome reported

Study characteristics

Methods

Study design: Historically controlled trial

Study grouping:

Methods: Participants were not on lipid medications within 2 months of the trial; therefore, no washout required. 3 months before‐and‐after study

Participants

Baseline Characteristics

2 mg

• n: 30

• Age (years): 60.5

• Males (n): 14

• Females (n): 16

• BMI: 23.8

• Total cholesterol: 5.54 mmol/L(214 mg/dL)

• LDL cholesterol: 3.60 mmol/L(139 mg/dL)

• HDL cholesterol: 1.12 mmol/L(43 mg/dL)

• Triglycerides: 1.94 mmol/L(172 mg/dL)

Included criteria: participants have primary hypertension, men and women aged 18 to 85 years.

Excluded criteria: people who were taking lipid‐lowering drugs, nonsteroidal anti‐inflammatory drugs, anticoagulants, angiotensin receptor antagonists; also with liver and kidney and other organ dysfunction; other cardiovascular diseases; having infectious diseases; acute and chronic inflammatory disease, connective tissue disease, cancer, diabetes, thyroid disease; pregnant and lactating women

Baseline Group Characteristics: There was no significant difference between the BMI and smoking status between groups

Interventions

Intervention Characteristics

2 mg

Outcomes

Total cholesterol

• Outcome type: Continuous

LDL cholesterol

• Outcome type: Continuous

HDL cholesterol

• Outcome type: Continuous

Triglycerides

• Outcome type: Continuous

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

Judgement Comment: Controlled before‐and‐after design

Allocation concealment (selection bias)

High risk

Judgement Comment: Controlled before‐and‐after design

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Judgement Comment: Lipid parameter measurements unlikely to be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Judgement Comment: Lipid parameters were measured in a remote laboratory.

Selective reporting (reporting bias)

Low risk

Judgement Comment: LDL‐cholesterol outcome was reported.

Other bias

Unclear risk

Judgement Comment: source of funding not reported

Incomplete outcome data (attrition bias) Total cholesterol

Low risk

All participants were included in the efficacy analysis.

Incomplete outcome data (attrition bias) LDL cholesterol)

Low risk

All participants were included in the efficacy analysis.

Incomplete outcome data (attrition bias) HDL cholesterol

Low risk

All participants were included in the efficacy analysis.

Incomplete outcome data (attrition bias) Triglycerides

Low risk

All participants were included in the efficacy analysis.

Blinding of outcome assessment (detection bias)WDAEs

High risk

No comparison possible

Selective reporting (reporting bias) for WDAEs

High risk

No WDAE outcome reported

Study characteristics

Methods

Study design: Historically controlled trial

Study grouping:

Methods: Washout period of 1 month;

3 months before‐and‐after trial

Participants

Baseline Characteristics

2 mg

• n: 34

• Age (years): 58.2

• Males (n): 20

• Females (n): 14

• Total cholesterol: 6.38 mmol/L (247 mg/dL)

• LDL cholesterol: 4.40 mmol/L (166 mg/dL)

• HDL cholesterol: 0.97 mmol/L (37.5 mg/dL)

• Triglycerides: 2.66 mmol/L (236 mg/dL)

• Included criteria: primary hyperlipidaemia, fasting levels of 5.72 mmol/L ≤ total cholesterol (TC) ≤ 12.7 mmol/L, 3.64 mmol/L ≤ LDL‐C ≤ 6.50 mmol/L, and TG < 4.52 mmol/L

• Excluded criteria: secondary hyperlipidaemia; acute coronary syndrome within 6 months, cerebrovascular accident, history of severe trauma or a history of major surgery; severe liver and kidney disease, alanine aminotransferase (ALT), aspartate aminotransferase (AST) exceeds the upper limit of normal value by 3 times, serum creatinine (Cr), urea nitrogen (BUN) more than twice the upper limit of normal; suffering from other serious disease (such as cancer, heart failure, respiratory failure, etc.); abnormal thyroid function; systolic blood pressure ≥ 180 mmHg after drug treatment for severe hypertension or diastolic blood pressure ≥ 110 mmHg; diabetes patients treated by drugs, fasting blood glucose after treatment ≥ 11.1mmol/L; drugs that may affect blood lipid metabolism (such as heparin, amiodarone, contraceptives, etc.); pregnancy, women who are breastfeeding, or women who are planning to become pregnant; those with muscle disease or unexplained serum creatine kinase of more than three times the upper limit of normal; history of allergies or serious adverse reactions to statins; mental disorders or participants who are uncooperative

• Baseline Group Characteristics: The treatment groups were well matched in terms of age, gender, and disease diagnosis

Interventions

Intervention Characteristics

2 mg

Outcomes

Total cholesterol

• Outcome type: Continuous

LDL cholesterol

• Outcome type: Continuous

HDL cholesterol

• Outcome type: Continuous

Triglycerides

• Outcome type: Continuous

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

Controlled before‐and‐after design

Allocation concealment (selection bias)

High risk

Controlled before‐and‐after design

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Lipid parameter measurements unlikely to be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Lipid parameters were measured in a remote laboratory.

Selective reporting (reporting bias)

Low risk

LDL‐cholesterol outcome was reported.

Other bias

Unclear risk

Source of funding not reported

Incomplete outcome data (attrition bias) Total cholesterol

Low risk

All participants were included in the efficacy analysis.

Incomplete outcome data (attrition bias) LDL cholesterol)

Low risk

All participants were included in the efficacy analysis.

Incomplete outcome data (attrition bias) HDL cholesterol

Low risk

All participants were included in the efficacy analysis.

Incomplete outcome data (attrition bias) Triglycerides

Low risk

All participants were included in the efficacy analysis.

Blinding of outcome assessment (detection bias)WDAEs

High risk

No comparison possible

Selective reporting (reporting bias) for WDAEs

High risk

No WDAE outcome reported

Study characteristics

Methods

Study design: Historically controlled trial

Study grouping:

Methods: 6‐8 week washout period, 4 week before‐and‐after trial with evening dosing

Participants

Baseline Characteristics

2 mg

• n: 233

• Males (n): 158

• Females (n): 75

• Age (years): 60.1

• Heterozygous Familial Hypercholesterolemia: 4

Included criteria: Patients of either gender were eligible for inclusion in the study if they were aged 18‐75 years and had primary hypercholesterolaemia or combined dyslipidaemia that was uncontrolled (LDL‐C ≥ 3.4 mmol/L [130 mg/dL] and ≤ 5.7mmol/L [220 mg/dL]; triglycerides ≤ 4.6 mmol/L [400 mg/dL]) despite dietary measures. In addition, patients were required to have at least two of the following cardiovascular risk factors: cigarette smoking; blood pressure of 140/90 mmHg or above or receiving antihypertensive therapy; a high‐density lipoprotein cholesterol (HDL‐C) concentration of 1 mmol/L (40 mg/dL) or below; a family history of CHD in a male or female first‐degree relative below 55 or below 65 years of age, respectively; age above 45 years in men or above 55 years in women. An HDL‐C concentration above 1.55 mmol/L (60 mg/dL) was considered to offset one risk factor. Patients who were receiving lipid‐modifying therapies were eligible for inclusion if such treatment was withdrawn at least 8 weeks before randomisation.

Excluded criteria: The principal exclusion criteria were homozygous familial hypercholesterolaemia, unstable medical conditions, or conditions associated with secondary dyslipidaemia, conditions that might affect drug pharmacokinetics, significant cardiovascular disease, or symptomatic heart failure (left ventricular ejection fraction 0.25) or cerebrovascular disease, uncontrolled or poorly controlled hypertension, uncontrolled diabetes (> 8% glycated haemoglobin), impaired liver or kidney function, or other serious medical conditions. Women of childbearing potential were required to have a negative pregnancy test at the start of the dietary run‐in period and before starting treatment, and to use adequate contraception throughout the study.

Baseline Group Characteristics: The two groups were well matched in terms of their baseline characteristics. The mean age of the patients was approximately 60 years, about two‐thirds were male, and all except one were white. The majority of patients (>80%) had primary hypercholesterolaemia, and approximately three‐quarters were at moderate or high cardiovascular risk according to the NCEP criteria.

Interventions

Intervention Characteristics

2 mg

Outcomes

LDL‐cholesterol

• Outcome type: Continuous

• Reporting: Fully reported

• Unit of measure: Percentage change from baseline

• Direction: Lower is better

• Data value: Change from baseline

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

Judgement Comment: Controlled before‐and‐after design

Allocation concealment (selection bias)

High risk

Judgement Comment: Controlled before‐and‐after design

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Judgement Comment: Lipid parameter measurements unlikely to be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Judgement Comment: Lipid parameters were measured in a remote laboratory.

Selective reporting (reporting bias)

Low risk

Judgement Comment: LDL‐cholesterol outcome was reported.

Other bias

High risk

Judgement Comment: The study was supported by Kowa Research Europe Ltd.

Incomplete outcome data (attrition bias) Total cholesterol

Low risk

[(236 ‐ 233)/236]*100 =1.3% participants were not included in the efficacy analysis.

Incomplete outcome data (attrition bias) LDL cholesterol)

Low risk

[(236 ‐ 233)/236]*100 =1.3% participants were not included in the efficacy analysis.

Incomplete outcome data (attrition bias) HDL cholesterol

Low risk

[(236 ‐ 233)/236]*100 =1.3% participants were not included in the efficacy analysis.

Incomplete outcome data (attrition bias) Triglycerides

Low risk

[(236 ‐ 233)/236]*100 =1.3% participants were not included in the efficacy analysis.

Blinding of outcome assessment (detection bias)WDAEs

High risk

No comparison possible

Selective reporting (reporting bias) for WDAEs

High risk

No WDAE outcome reported

Study characteristics

Methods

Study design: Historically controlled trial

Study grouping:

Method: 6‐8 week washout period, 12 week before‐and‐after study with evening dosing

Participants

Baseline Characteristics

2 mg

• n: 275

• Males (n): 155

• Females (n): 120

• BMI : 29.4

• LDL cholesterol: 143 mg/dL (3.7 mmol/L)

Included criteria: Eligible patients were aged 18 – 75 years with type 2 diabetes [haemoglobin A1c (HbA1c) ≤ 7.5%] and combined dyslipidaemia [plasma LDL‐C ≥ 100 and ≤ 220 mg/dL (≥ 2.6 and ≤ 5.7 mmol/L) and triglycerides (TG) ≥ 150 mg/dL ( ≥1.7 mmol/L)], despite dietary therapy, and were receiving an oral antidiabetic treatment (not including glitazones) or insulin. Eligible patients had a body mass index (BMI) of not more than 35 kg/m², and women of childbearing potential had to use reliable contraception.

Excluded criteria: homozygous familial hypercholesterolaemia; other conditions with potential to cause secondary dyslipidaemia, including human immunodeficiency virus infection; HbA1c more than 7.5%; significant cardiovascular disease; history of cerebrovascular disease, neoplastic disease within 10 years, unexplained increased serum creatine kinase (CK) of more than five times the upper limit of the reference range (ULRR); systolic blood pressure above 160 mmHg and diastolic blood pressure above 90 mmHg; history of muscular or neuromuscular disease; and history of resistance to lipid‐lowering therapy or use of supplements that affect lipid metabolism

Baseline Group Characteristics: Baseline characteristics were generally well matched across randomised treatment groups in the core study. Most patients were Caucasian (88%) and male (57%), with a mean age of 59 years. All patients were in the NCEP high‐risk category; most were hypertensive (77%) and 49% had previously received a lipid‐modifying therapy.

Interventions

Intervention Characteristics

2 mg

Outcomes

LDL cholesterol

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Lower is better

• Data value: Change from baseline

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

Judgement Comment: Controlled before‐and‐after design

Allocation concealment (selection bias)

High risk

Judgement Comment: Controlled before‐and‐after design

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Judgement Comment: Lipid parameter measurements unlikely to be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Judgement Comment: Lipid parameters were measured in a remote laboratory.

Selective reporting (reporting bias)

Low risk

Judgement Comment: LDL‐cholesterol outcome was reported.

Other bias

High risk

Judgement Comment: Kowa Research Europe Ltd. supported this trial.

Incomplete outcome data (attrition bias) Total cholesterol

Low risk

[(279 ‐ 274)/279]*100 = 1.8% were not included in the efficacy analysis.

Incomplete outcome data (attrition bias) LDL cholesterol)

Low risk

[(279 ‐ 274)/279]*100 = 1.8% were not included in the efficacy analysis.

Incomplete outcome data (attrition bias) HDL cholesterol

Low risk

[(279 ‐ 274)/279]*100 = 1.8% were not included in the efficacy analysis.

Incomplete outcome data (attrition bias) Triglycerides

Low risk

[(279 ‐ 274)/279]*100 = 1.8% were not included in the efficacy analysis.

Blinding of outcome assessment (detection bias)WDAEs

High risk

No comparison possible

Selective reporting (reporting bias) for WDAEs

High risk

No WDAE outcome reported

Study characteristics

Methods

Study design: Historically controlled trial

Study grouping:

Method: No washout required because no subject was receiving lipid medications within 3 months of trial, 3‐month before‐and‐after trial

Participants

Baseline Characteristics

4 mg

• n: 48

• Age (years): 58.2

• Males (n): 14

• Females (n): 34

• BMI: 24.8

• Total cholesterol: 246.5 mg/dL (6.37 mmol/L)

• LDL cholesterol: 168.8 mg/dL (4.37 mmol/L)

• HDL cholesterol: 56.0 mg/dL (1.45 mmol/L)

• Triglycerides: 144.1 mg/dL (1.63mmol/L)

Included criteria: age from 40 to 80 years, statin‐naïve subjects, and low‐density lipoprotein cholesterol (LDL‐C) ≥ 130 mg/dL with more than or equal to two major risk factors for coronary heart disease (CHD) or LDL‐C ≥ 160 mg/dL with less than two risk factors. Major risk factors for CHD include ≥ 45 years of age for men or ≥ 55 years of age for women, family history of premature CHD (CHD in male first‐degree relative ＜ 55 years or in female first‐degree relative ＜ 65 years), current cigarette smoking, blood pressure (BP) ≥ 140/90 mmHg or on antihypertensive medication, and high‐density lipoprotein cholesterol (HDL‐C) ＜ 40 mg/dL

Excluded criteria: hospitalisation for acute coronary syndrome or cerebrovascular disease within the previous 2 months; the use of statin or other lipid‐lowering medication within the previous 3 months; impaired hepatic function or a history of liver disease; chronic renal failure; a history of malignancy; any known contraindication to statin therapy, such as statin allergy, ciclosporin use, pregnancy, breastfeeding, myopathy, or lactose intolerance; and failure to obtain informed consent from participants

Baseline Group Characteristics: The mean age was 58 ±8 years, and female predominance was observed (70.8%, [34/48]). Thirty‐two patients (66.7%) had hypertension, and 8 patients (16.7%) had diabetes. None of the patients had coronary artery disease. Of the patients, 25 (52.1%) were taking angiotensin‐converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB), 10 (20.8%) were taking beta blockers, and 15 (31.3%) were taking calcium‐channel blockers (CCB).

Interventions

Intervention Characteristics

4 mg

Outcomes

Total cholesterol

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Lower is better

LDL cholesterol

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Lower is better

HDL cholesterol

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Higher is better

Triglycerides

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Lower is better

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

Judgement Comment: Controlled before‐and‐after design

Allocation concealment (selection bias)

High risk

Judgement Comment: Controlled before‐and‐after design

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Judgement Comment: Lipid parameter measurements unlikely to be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Judgement Comment: Lipid parameters were measured in a remote laboratory.

Selective reporting (reporting bias)

Low risk

Judgement Comment: LDL‐cholesterol outcome was reported.

Other bias

High risk

Judgement Comment: Study was supported by grants from Il‐dong Pharmaceutical Co. Ltd. (Republic of Korea)

Incomplete outcome data (attrition bias) Total cholesterol

High risk

Judgement Comment: (60 ‐ 48)*100/60 = 20% were not included n the efficacy analysis.

Incomplete outcome data (attrition bias) LDL cholesterol)

High risk

Judgement Comment: (60 ‐ 48)*100/60 = 20% were not included n the efficacy analysis.

Incomplete outcome data (attrition bias) HDL cholesterol

High risk

Judgement Comment: (60 ‐ 48)*100/60 = 20% were not included n the efficacy analysis.

Incomplete outcome data (attrition bias) Triglycerides

High risk

Judgement Comment: (60 ‐ 48)*100/60 = 20% were not included n the efficacy analysis.

Blinding of outcome assessment (detection bias)WDAEs

High risk

Judgement Comment: No comparison possible

Selective reporting (reporting bias) for WDAEs

High risk

No WDAE outcome reported

Study characteristics

Methods

Study design: Historically controlled trial

Study grouping:

Method: No washout required because no participant received lipid medications, 4 weeks before‐and‐after trial

Participants

Baseline Characteristics

2 mg

• n: 97

• Males (n): 66

• Females (n): 31

• Total cholesterol: 5.73 mmol/L (222 mg/dL)

• LDL cholesterol: 3.76 mmol/L (145 mg/dL)

• HDL cholesterol: 1.18 mmol/L (45.6 mg/dL)

• Triglycerides: 2.30 mmol/L (204 mg/dL)

• Age (years): 55.5

Included criteria: Adult subjects, aged 25 to 75 years, with elevated ALT concentrations (≥ 1.25 times and ≤ 2.5 times the upper limit of the normal range [ULN]; 40 IU/L) were recruited from the lipid clinics of 10 major hospitals in Korea. All subjects were non‐alcoholics and serologically negative for viral hepatitis markers. None had been treated with statins for more than 3 months before screening, and all had basal fasting LDL‐C concentration levels ≥ 3.36 mmol/L (≥ 130 mg/dL).After 2 weeks of an intervention‐free screening period, subjects were re‐evaluated, including by measurements of serum ALT levels. Subjects who did not meet any of the exclusion criteria were grouped into those with persistently elevated (> 1.25 times and ≤ 2.5 times ULN; 50–100 IU/L) and reduced (50 IU/L) concentrations.

Excluded criteria: Overt and irreversible liver cirrhosis, serologically positive for viral markers or active viral hepatitis, cholestatic features (serum bilirubin > 2 X ULN), fasting triglyceride levels ≥ 4.52 mmol/L (400mg/dL), acute or unstable conditions, including a recent history (3 months) of myocardial infarction, advanced heart failure (New York Heart Association class III‐IV), renal dysfunction (serum creatinine ≥ 2.0 mg/dL), uncontrolled hypertension (DBP ≥ 100 mmHg), and thyroid dysfunction (TSH ≥ 1.5 X ULN). Medications prohibited from 1 month before the screening period until the completion of study included drugs that could potentially improve liver function test results (betaine, thiazolidinediones), those that could induce significant hepatic damage (synthetic estrogens, androgen, oral contraceptives, amiodarone, tamoxifen, erythromycin, tetracycline, sulfa antibiotics, methotrexate, perhexiline maleate, valproic acid, cocaine, zidovudine, didanosine, fialuridine, isoniazid, rifampicin, other anti‐tuberculosis medications, trazodone, nefazodone, venlafaxine, chlorpromazine, quinidine, gemfibrozil, herb medication), those that could affect lipid profiles (other HMG‐CoA reductase inhibitors, fibrates, niacin, ezetimibe, steroids, anti‐obesity drugs), and those known to have serious drug interactions with statins (ketoconazole, itraconazole, erythromycin, clarithromycin, cyclosporin, norethindrone, ethyl estradiol).

Baseline Group Characteristics: Of these subjects, 129 were male and 60 were female, their mean age was 55.1 years, and 28% had been diagnosed with diabetes, 68% with hypertension, and 72% with metabolic syndrome. All demographic features; habits such as exercise, smoking, and drinking; and medication profiles were similar between the two groups.

Interventions

Intervention Characteristics

2 mg

Outcomes

Total cholesterol

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Lower is better

LDL cholesterol

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Lower is better

HDL cholesterol

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Higher is better

Triglycerides

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Lower is better

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

Judgement Comment: Controlled before‐and‐after design

Allocation concealment (selection bias)

High risk

Judgement Comment: Controlled before‐and‐after design

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Judgement Comment: Lipid parameter measurements unlikely to be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Judgement Comment: Lipid parameters were measured in a remote laboratory.

Selective reporting (reporting bias)

Low risk

Judgement Comment: LDL‐cholesterol outcome was reported.

Other bias

High risk

Judgement Comment: The study was supported by JW Pharmaceutical Co, Korea.

Incomplete outcome data (attrition bias) Total cholesterol

High risk

[(103 ‐ 88)/103)]*100 = 14.6% were not included in the efficacy analysis.

Incomplete outcome data (attrition bias) LDL cholesterol)

High risk

[(103 ‐ 88)/103)]*100 = 14.6% were not included in the efficacy analysis.

Incomplete outcome data (attrition bias) HDL cholesterol

High risk

[(103 ‐ 88)/103)]*100 = 14.6% were not included in the efficacy analysis.

Incomplete outcome data (attrition bias) Triglycerides

High risk

[(103 ‐ 88)/103)]*100 = 14.6% were not included in the efficacy analysis.

Blinding of outcome assessment (detection bias)WDAEs

High risk

No comparison possible

Selective reporting (reporting bias) for WDAEs

High risk

No WDAE outcome reported

Study characteristics

Methods

Study design: Historically controlled trial

Study grouping: Parallel group

Method: 3 month dietary run‐in period, 12‐week before‐and‐after study with morning dosing

Participants

Baseline Characteristics

1 mg

• n: 7

• Males (n): 7

• Age (years): 12.0

• BMI: 19.0

• Heterozygous FH: 7

• Total cholesterol: 317.9 mg/dL (8.22 mmol/L)

• LDL cholesterol: 245.4 mg/dL (6.35 mmol/L)

• HDL cholesterol: 58.6 mg/dL (1.52 mmol/L)

• Triglycerides: 69.6 mg/dL (0.786 mmol/L)

1 mg then titrated to 2 mg at week 4

• n: 7

• Males (n): 7

• Age (years): 11.6

• BMI: 18.3

• Heterozygous FH: 7

• Total cholesterol: 344.4 mg/dL (1.81 mmol/L)

• LDL cholesterol: 269.6 mg/dL (6.97 mmol/L)

• HDL cholesterol: 56.6 mg/dL (1.46 mmol/L)

• Triglycerides: 91.3 mg/dL (1.03 mmol/L)

Overall

• n: 14

• Males (n): 14

• Age (years): 11.8

• BMI: 18.7

• Heterozygous FH: 14

Included criteria: (1) patients with an LDL‐C level of ≥ 190 mg/dL or LDL‐C level of ≥ 160 mg/dL with one or more of the following risk factors, a family history of coronary artery disease (relation in the second degree), obesity (obesity index ≥ 20%), type 2 diabetes, hypertension (systolic blood pressure ≥ 125 mmHg or diastolic blood pressure ≥ 70 mmHg) and a low HDL cholesterol level ( ＜ 40 mg/dL); (2) Japanese male children 10 to 15 years of age inclusive at the time of informed consent; (3) patients who had received diet therapy for at least three months before screening based on a physician’s instructions or those whose diet for at least three months before screening was judged by the investigator not to require more intensive dietary restrictions (in either case, the patients were required to have received a fixed regimen of diet or diet/exercise therapy for at least four weeks before screening); (4) outpatients; and (5) patients for whom written informed consent was obtained from the patients themselves and their parents or guardians

Excluded criteria: (1) patients with homozygous familial hypercholesterolaemia; (2) patients with secondary hyperlipidaemia; (3) patients on apheresis therapy; (4) patients who had recently experienced a cerebrovascular disorder, anginal attack or myocardial infarction; (5) patients with severe hepatic or renal disorders, poor glycaemic control, severe hypertension, a history of allergies to drugs or serious adverse drug reactions (ADRs); (6) patients who had participated in other clinical trial(s) and received investigational drug(s) within 12 weeks before screening; and (7) patients judged inappropriate for the study by the investigator

Baseline Group Characteristics: The mean age was 11.8 years, the mean height was 147.6 cm, and the mean weight was 41.1 kg. The patient characteristics were generally similar between 1 mg and 2 mg treatment groups, except for the obesity index.

Interventions

Intervention Characteristics

1 mg

1 mg then titrated to 2 mg at week 4

Both Groups

Outcomes

Total cholesterol

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Lower is better

LDL cholesterol

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Lower is better

HDL cholesterol

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Higher is better

Triglycerides

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Lower is better

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

Judgement Comment: Controlled before‐and‐after design

Allocation concealment (selection bias)

High risk

Judgement Comment: Controlled before‐and‐after design

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Judgement Comment: Lipid parameter measurements unlikely to be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Judgement Comment: Lipid parameters were measured in a remote laboratory.

Selective reporting (reporting bias)

Low risk

Judgement Comment: LDL‐cholesterol outcome was reported.

Other bias

High risk

Judgement Comment: Kowa Co. Ltd funded this trial.

Incomplete outcome data (attrition bias) Total cholesterol

Low risk

All participants were included in the efficacy analysis.

Incomplete outcome data (attrition bias) LDL cholesterol)

Low risk

All participants were included in the efficacy analysis.

Incomplete outcome data (attrition bias) HDL cholesterol

Low risk

All participants were included in the efficacy analysis.

Incomplete outcome data (attrition bias) Triglycerides

Low risk

All participants were included in the efficacy analysis.

Blinding of outcome assessment (detection bias)WDAEs

High risk

No comparison possible

Selective reporting (reporting bias) for WDAEs

High risk

No WDAE outcome reported

Study characteristics

Methods

Study design: Historically controlled trial

Study grouping:

Method: Participants were not on any lipid medications, therefore no washout required, 3‐month before‐and‐after study

Participants

Baseline Characteristics

2 mg

• n: 40

• Age (years): 74.6

• Males (n): 26

• Females (n): 14

• BMI: 24

• Total cholesterol: 4.58 mmol/L (177 mg/dL)

• LDL cholesterol: 2.97 mmol/L (115 mg/dL)

• HDL cholesterol: 1.13 mmol/L (44 mg/dL)

• Triglycerides: 1.75 mmol/L (155 mg/dL)

Included criteria: Age > 60 years of age, conformity to the 1999 World Health Organization (WHO) criteria for the diagnosis of type 2 diabetes, blood glucose resulting in a HbA1c of 7%, stable blood sugar, fasting blood glucose (FBS) 70 mmol/L blood glucose, 2 h after three meals (PBC) 11.1 mmoI/L, not to have taken statins and other lipid‐regulating drugs within one month, expresses the intention of both patients and their family members, and signed informed consent

Excluded criteria: type 1 diabetes, uncooperative, poor compliance, hypersensitivity to pitavastatin and atorvastatin, homozygous familial hypercholesterolaemia, patients with active liver disease or unexplained persistent transaminase elevation (alanine aminotransferase and/or aspartate aminotransferase are 3 times greater than normal), patients taking immunosuppressants such as cyclosporine, severe cases of kidney disease, severe cardiovascular and cerebrovascular diseases (such as myocardial infarction, acute cerebral infarction, acute heart failure, etc.), severe infection, trauma, stress ulcer hyperthyroidism, malignancy, diabetic ketosis, diabetic patients with non‐ketotic hyperosmolar coma or patients with psychiatric symptoms and patients receiving glucocorticoids and postoperative patients

Baseline Group Characterisitcs: Baseline characteristics were generally well matched across age, gender, smoking, BMI, drinking history, drug use, and disease diagnosis

Interventions

Intervention Characteristics

2 mg

Outcomes

Total cholesterol

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Lower is better

LDL cholesterol

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Lower is better

HDL cholesterol

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Higher is better

Triglycerides

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Lower is better

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

Judgement Comment: Controlled before‐and‐after design

Allocation concealment (selection bias)

High risk

Judgement Comment: Controlled before‐and‐after design

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Judgement Comment: Lipid parameter measurements unlikely to be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Judgement Comment: Lipid parameters were measured in a remote laboratory.

Selective reporting (reporting bias)

Low risk

Judgement Comment: LDL‐cholesterol outcome was reported.

Other bias

Unclear risk

Judgement Comment: Source of funding was not reported.

Incomplete outcome data (attrition bias) Total cholesterol

Unclear risk

[(40 ‐ 36)/40)]*100 = 10% participants were not included in the efficacy analysis.

Incomplete outcome data (attrition bias) LDL cholesterol)

Unclear risk

[(40 ‐ 36)/40)]*100 = 10% participants were not included in the efficacy analysis.

Incomplete outcome data (attrition bias) HDL cholesterol

Unclear risk

[(40 ‐ 36)/40)]*100 = 10% participants were not included in the efficacy analysis.

Incomplete outcome data (attrition bias) Triglycerides

Unclear risk

[(40 ‐ 36)/40)]*100 = 10% participants were not included in the efficacy analysis.

Blinding of outcome assessment (detection bias)WDAEs

High risk

No comparison possible

Selective reporting (reporting bias) for WDAEs

High risk

No WDAE outcome reported

Study characteristics

Methods

Study design: Historically controlled trial

Study grouping:

Method: No participants were receiving lipid medications, therefore, washout period not required; 3‐month before‐and‐after trial

Participants

Baseline Characteristics

2 mg

• n: 15

• Males: 10

• Females: 5

• Age (years): 43.7

• Total cholesterol: 242.8 mg/dL (6.28 mmol/L)

Included criteria: 15 men and women with hypercholesterolaemia

Excluded criteria: alcohol consumption of more than 20 g per week; evidence of pregnancy, treatment with corticosteroid, and hormone replacement therapy. Subjects using lipid‐lowering medication or food enriched with functional plant stanols or sterols were excluded from the study. Subjects with positive test results for the following disorders were also excluded: secondary causes of steatohepatitis and drug‐induced liver injury, viral hepatitis, autoimmune hepatitis, primary biliary cirrhosis, a‐1‐antitrypsin deficiency, haemochromatosis, Wilson’s disease, and biliary obstruction.

Baseline Group Characteristics: The mean ages and ratios of male/female subjects were not significantly different between the control and NAFLD groups.

Interventions

Intervention Characteristics

2 mg

Outcomes

Total cholesterol

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Lower is better

• Data value: Change from baseline

Notes

Stephen P on 27/01/2018 11:00
Included
Post hoc of Hyogo 2011 trial

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

Judgement Comment: Controlled before‐and‐after design

Allocation concealment (selection bias)

High risk

Judgement Comment: Controlled before‐and‐after design

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Judgement Comment: Lipid parameter measurements unlikely to be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Judgement Comment: Lipid parameters were measured in a remote laboratory.

Selective reporting (reporting bias)

High risk

Judgement Comment: LDL‐C outcome was not reported.

Other bias

Low risk

Judgement Comment: This study was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

Incomplete outcome data (attrition bias) Total cholesterol

Low risk

All participants were included in the efficacy analysis.

Incomplete outcome data (attrition bias) LDL cholesterol)

High risk

LDL cholesterol was not reported.

Incomplete outcome data (attrition bias) HDL cholesterol

High risk

HDL cholesterol was not reported.

Incomplete outcome data (attrition bias) Triglycerides

High risk

Triglycerides were not reported.

Blinding of outcome assessment (detection bias)WDAEs

High risk

No comparison possible

Selective reporting (reporting bias) for WDAEs

High risk

No WDAE outcome reported

Study characteristics

Methods

Study design: Historically controlled trial

Study grouping:

Method: 4‐8 week placebo washout period; 8‐week before‐and‐after study with evening dosing

Participants

Baseline Characteristics

2 mg

• n: 30

• Males (n): 15

• Females (n): 15

• Total cholesterol: 8.80 mmol/L (340 mg/dL)

• LDL cholesterol: 6.81 mmol/L (263 mg/dL)

• HDL cholesterol: 1.31 mmol/L (51 mg/dL)

• Triglycerides: 1.99 mmol/L (176 mg/dL)

Included criteria: 30 patients (15 men and 15 women, aged 51 ± 13 [mean ± SD] years) with heterozygous FH. All patients fulfilled the diagnostic criteria: primary hypercholesterolaemia (> 230 mg/dL) with tendon xanthoma or first‐degree relatives of previously diagnosed heterozygous FH patients showing primary hypercholesterolaemia (> 230 mg/dL). The mean ± SD of body mass index was 23.9 ± 2.9 kg/m². Coronary artery disease had already been documented in 9 patients (30%), and no patient had cerebral atherosclerotic vascular disease.

Excluded criteria: not reported.

Baseline Group Characteristics: The study population consisted of 30 patients (15 men and 15 women, aged 51±13 [mean ± SD] years) with heterozygous FH. All patients fulfilled our diagnostic criteria: primary hypercholesterolaemia ( > 230 mg/dl) with tendon xanthoma or first‐degree relatives of previously diagnosed heterozygous FH patients showing primary hypercholesterolaemia (> 230 mg/dl). The mean ± SD of body mass index was 23.9 ± 2.9 kg/m² . Coronary artery disease had already been documented in 9 patients (30%), and no patient had cerebral atherosclerotic vascular disease.

Interventions

Intervention Characteristics

2 mg

• evening dosing

Outcomes

Total cholesterol

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Lower is better

LDL cholesterol

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Lower is better

HDL cholesterol

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Higher is better

Triglycerides

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Lower is better

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

Judgement Comment: Controlled before‐and‐after design

Allocation concealment (selection bias)

High risk

Judgement Comment: Controlled before‐and‐after design

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Judgement Comment: Lipid parameter measurements unlikely to be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Judgement Comment: Lipid parameters were measured in a remote laboratory.

Selective reporting (reporting bias)

Low risk

Judgement Comment: LDL‐cholesterol outcome was reported.

Other bias

Unclear risk

Judgement Comment: source of funding was not reported.

Incomplete outcome data (attrition bias) Total cholesterol

Low risk

All participants were included in the efficacy analysis.

Incomplete outcome data (attrition bias) LDL cholesterol)

Low risk

All participants were included in the efficacy analysis.

Incomplete outcome data (attrition bias) HDL cholesterol

Low risk

All participants were included in the efficacy analysis.

Incomplete outcome data (attrition bias) Triglycerides

Low risk

All participants were included in the efficacy analysis.

Blinding of outcome assessment (detection bias)WDAEs

High risk

No comparison possible

Selective reporting (reporting bias) for WDAEs

High risk

No WDAE outcome reported

Study characteristics

Methods

Study design: Historically controlled trial

Study grouping:

Method: Participants were not on any medication; no washout required; 4‐week before‐and‐after trial

Participants

Baseline Characteristics

2 mg

• n: 10

• Males (n): 10

• Females (n): 0

• Total cholesterol: 197.9 mg/dL (5.12 mmol/L)

• LDL cholesterol: 121.5 mg/dL (3.14 mmol/L)

• HDL cholesterol: 56.6 mg/dL (1.46 mmol/L)

Included criteria: Japanese men, who agreed to undergo pitavastatin treatment and mixed meal test, were involved in this study (n = 10;age: 33.9 ± 10.1 years; body height 172.0 ± 4.3 cm; body weight 80.2 ± 25.3 kg; body mass index (BMI) 27.0 ± 8.3kg/m²; waist circumference 88.5 ± 18.9 cm)

Excluded criteria: not reported.

Baseline Group Characteristics: Japanese men, (n = 10; age 33.9 ± 10.1 years; body height 172.0 ± 4.3 cm; body weight 80.2 ± 25.3 kg; body mass index (BMI) 27.0 ± 8.3 kg/m2 ; waist circumference 88.5 ± 18.9 cm). None of them had received medication.

Interventions

Intervention Characteristics

2 mg

Outcomes

Total cholesterol

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Lower is better

LDL cholesterol

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Lower is better

HDL cholesterol

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Higher is better

Notes

Stephen P on 02/02/2018 08:13
Outcomes
Triglyceride outcome was not included in the efficacy analysis because the values were expressed as medians.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

Judgement Comment: Controlled before‐and‐after design

Allocation concealment (selection bias)

High risk

Judgement Comment: Controlled before‐and‐after design

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Judgement Comment: Lipid parameter measurements unlikely to be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Judgement Comment: Lipid parameters were measured in a remote laboratory.

Selective reporting (reporting bias)

Low risk

Judgement Comment: LDL‐cholesterol outcome was reported.

Other bias

Unclear risk

Judgement Comment: source of funding was not reported.

Incomplete outcome data (attrition bias) Total cholesterol

Low risk

All participants were included in the efficacy analysis.

Incomplete outcome data (attrition bias) LDL cholesterol)

Low risk

All participants were included in the efficacy analysis.

Incomplete outcome data (attrition bias) HDL cholesterol

Low risk

All participants were included in the efficacy analysis.

Incomplete outcome data (attrition bias) Triglycerides

High risk

Triglyceride data were not included in the efficacy analysis.

Blinding of outcome assessment (detection bias)WDAEs

High risk

No comparison possible

Selective reporting (reporting bias) for WDAEs

High risk

No WDAE outcome reported

Study characteristics

Methods

Study design: Historically controlled trial

Study grouping:

Method: 4‐week dietary washout period; 4‐week before‐and‐after study

Participants

Baseline Characteristics

2 mg

• n: 110

• Age (years): 59.6

• Males (n): 35

• Females (n): 75

• BMI: 25.2

• Total cholesterol: 239 mg/dL (6.18 mmol/L)

• LDL cholesterol: 159 mg/dL (4.11 mmol/L)

• HDL cholesterol: 52 mg/dL (1.34 mmol/L)

• Triglycerides: 142 mg/dL (1.60 mmol/L)

Included criteria: Korean men and women aged 20 to 79 years who had untreated hypercholesterolaemia

Excluded criteria: Pregnant and breastfeeding women were excluded. Other exclusion criteria were current use of lipid‐lowering therapy, uncontrolled diabetes mellitus (fasting plasma glucose concentration > 180 mg/dL), uncontrolled hypertension (diastolic blood pressure > 115 mm Hg), a history of cerebrovascular disease or myocardial infarction within 3 months of enrolment, congestive heart failure, a serum creatinine concentration > 2.0 mg/dL, hepatic dysfunction (transaminase levels > 2.5 times the upper limit of normal [ULN]), or an unexplained serum creatine kinase (CK) elevation > 2.5 times the ULN

Baseline Characteristics: The characteristics of the 2 groups were similar at baseline.

Interventions

Intervention Characteristics

2 mg

Outcomes

Total cholesterol

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Lower is better

LDL cholesterol

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Lower is better

HDL cholesterol

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Higher is better

Triglycerides

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Lower is better

Notes

Nima Alaeiilkhchi on 27/01/2018 11:48
Included
We calculated the incomplete outcome data based on best estimates from the results.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

Judgement Comment: Controlled before‐and‐after design

Allocation concealment (selection bias)

High risk

Judgement Comment: Controlled before‐and‐after design

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Judgement Comment: Lipid parameter measurements unlikely to be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Judgement Comment: Lipid parameters were measured in a remote laboratory.

Selective reporting (reporting bias)

Low risk

Judgement Comment: LDL‐cholesterol outcome was reported.

Other bias

High risk

Judgement Comment: Study was funded by Choongwae Pharma Corp. Seoul, Republic of Korea.

Incomplete outcome data (attrition bias) Total cholesterol

High risk

[(136 ‐ 110)/136] X 100 = 19.1% were not included in the efficacy analysis.

Incomplete outcome data (attrition bias) LDL cholesterol)

High risk

[(136 ‐ 110)/136] X 100 = 19.1% were not included in the efficacy analysis.

Incomplete outcome data (attrition bias) HDL cholesterol

High risk

[(136 ‐ 110)/136] X 100 = 19.1% were not included in the efficacy analysis.

Incomplete outcome data (attrition bias) Triglycerides

High risk

[(136 ‐ 110)/136] X 100 = 19.1% were not included in the efficacy analysis.

Blinding of outcome assessment (detection bias)WDAEs

High risk

No comparison possible

Selective reporting (reporting bias) for WDAEs

High risk

No WDAE outcome reported

Study characteristics

Methods

Study design: Historically controlled trial

Study grouping:

Method: 4‐week dietary lead‐in period; 12‐week before‐and‐after study

Participants

Baseline Characteristics

2 mg

• n: 112

• Age (years): 58.7

• Males (n): 69

• Females (n): 43

• BMI: 26.6

• Total cholesterol: 213 mg/dL (5.51 mmol/L)

• LDL cholesterol: 149.6 mg/dL (3.87 mmol/L)

• HDL cholesterol: 48.7 mg/dL (1.26 mmol/L)

• Triglycerides: 156 mg/dL (1.76 mmol/L)

Included criteria: Eligible patients were men and women aged 20 or older with fasting LDL‐C higher than 100 mg/dL. In addition, to be considered “high‐risk”, a patient had to meet at least one of the following criteria (NCEP ATP III guideline): documented CHD; type 2 DM; the patient had fewer than 2 risk factors (other than LDL) present in the following items without CHD or a CHD risk equivalent, a 10‐year (short‐term) CHD risk had to be assessed with a Framingham score > 20%: female: ≥ 55 years old, or male: ≥ 45 years old; fasting high‐density lipoprotein cholesterol (HDL‐C) 40 mg/dL; a family history of premature CHD (CHD in first‐degree male relative 55 years; CHD in first‐degree female relative 65 years); hypertension (BP ≥ 140/90 mm Hg or treated with anti‐hypertensive agents); HDL‐C ≥ 60 mg/dL counted as a“negative” risk factor; its presence removed one risk factor from the total count.

Excluded criteria: a history of hypersensitivity to statins, hepatic dysfunction [aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 100 IU/L], suspected hepatic metabolism disorders or biliary obstruction (acute hepatitis, acute exacerbation of chronic hepatitis, liver cirrhosis, liver cancer and jaundice), or renal dysfunction (serum creatinine > 1.5 mg/dL), pregnancy, possible pregnancy, or breastfeeding and poorly controlled diabetes (HbA1C > 9.0%)

Baseline Group Characteristics: The characteristics of the 2 groups were similar at baseline.

Interventions

Intervention Characteristics

2 mg

Outcomes

Total cholesterol

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Lower is better

LDL cholesterol

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Lower is better

HDL cholesterol

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Higher is better

Triglycerides

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Lower is better

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

Judgement Comment: Controlled before‐and‐after design

Allocation concealment (selection bias)

High risk

Judgement Comment: Controlled before‐and‐after design

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Judgement Comment: Lipid parameter measurements unlikely to be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Judgement Comment: Lipid parameters were measured in a remote laboratory.

Selective reporting (reporting bias)

Low risk

Judgement Comment: LDL‐cholesterol outcome was reported.

Other bias

Low risk

Judgement Comment: The associated study (Lin 2014) was partly supported by research grants V101B‐023, V102B‐048 and V103B‐019 toL.Y. Lin. from the Taipei Veterans General Hospital, Taipei, Taiwan. Kowa company supplied the medicine for the clinical trial.

Incomplete outcome data (attrition bias) Total cholesterol

High risk

[(113 ‐ 94)/113]*100 = 16.8% were not included in the efficacy analysis.

Incomplete outcome data (attrition bias) LDL cholesterol)

High risk

[(113 ‐ 94)/113]*100 = 16.8% were not included in the efficacy analysis.

Incomplete outcome data (attrition bias) HDL cholesterol

High risk

[(113 ‐ 94)/113]*100 = 16.8% were not included in the efficacy analysis.

Incomplete outcome data (attrition bias) Triglycerides

High risk

[(113 ‐ 94)/113]*100 = 16.8% were not included in the efficacy analysis.

Blinding of outcome assessment (detection bias)WDAEs

High risk

No comparison possible

Selective reporting (reporting bias) for WDAEs

High risk

No WDAE outcome reported

Study characteristics

Methods

Study design: Historically controlled trial

Study grouping:

Method: No participant received lipid medications within 3 months of the trial, therefore, no washout required; 3‐month before‐and‐after study

Participants

Baseline Characteristics

1 mg

• n: 63

• Age (years): 59.5

• Males (n): 38

• Females (n): 25

• BMI: 24.7

• Total cholesterol: 253.86 mg/dL (6.56 mmol/L)

• LDL cholesterol: 160.37 mg/dL (4.15 mmol/L)

• HDL cholesterol: 58.38 mg/dL (1.51 mmol/L)

• Triglycerides: 175.87 mg/dL (1.99 mmol/L)

Included criteria: 101 Japanese patients (57 men and 44 women, mean age 58.58 ± 12.0 years) with untreated hypercholesterolaemia, who attended the clinic of Rakuwakai Otowa Hospital between March 2006 and December 2006, were selected for this study. The diagnosis of hypercholesterolaemia was established on the basis of laboratory findings, including an elevated serum total cholesterol (TC) level (> 220 mg/dL) and an elevated serum low density lipoprotein cholesterol (LDL‐C) level (> 140 mg/dL).

Excluded criteria: current smokers and those who had a history of fractures and/or of other diseases (type 1 diabetes mellitus, liver disease, renal dysfunction, malignancy, hyperthyroidism, hyperparathyroidism, hypercortisolism, or hypogonadism) and those taking medications (active vitamin D3, bisphosphonates, calcitonin, selective oestrogen receptor modulators, estrogens, testosterones, steroids, thyroid hormones, diuretics, heparin or anticonvulsants) that could influence bone metabolism

Baseline Group Characteristics: At baseline, all differences between group A and group B were non significant.

Interventions

Intervention Characteristics

1 mg

Outcomes

Total cholesterol

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Lower is better

LDL cholesterol

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Lower is better

HDL cholesterol

• Outcome type: ContinuousOutcome

• Unit of measure: Percentage change from baseline

• Direction: Higher is better

Triglycerides

• Outcome type: ContinuousOutcome

• Unit of measure: Percentage change from baseline

• Direction: Lower is better

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

Judgement Comment: Controlled before‐and‐after design

Allocation concealment (selection bias)

High risk

Judgement Comment: Controlled before‐and‐after design

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Judgement Comment: Lipid parameter measurements unlikely to be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Judgement Comment: Lipid parameters were measured in a remote laboratory.

Selective reporting (reporting bias)

Low risk

Judgement Comment: LDL‐C outcome was reported.

Other bias

Unclear risk

Judgement Comment: Source of funding was not reported.

Incomplete outcome data (attrition bias) Total cholesterol

Low risk

[(66 ‐ 63)/66]*100 = 4.5% were not included in the efficacy analysis.

Incomplete outcome data (attrition bias) LDL cholesterol)

Low risk

[(66 ‐ 63)/66]*100 = 4.5% were not included in the efficacy analysis.

Incomplete outcome data (attrition bias) HDL cholesterol

Low risk

[(66 ‐ 63)/66]*100 = 4.5% were not included in the efficacy analysis.

Incomplete outcome data (attrition bias) Triglycerides

Low risk

[(66 ‐ 63)/66]*100 = 4.5% were not included in the efficacy analysis.

Blinding of outcome assessment (detection bias)WDAEs

High risk

No comparison possible

Selective reporting (reporting bias) for WDAEs

High risk

No WDAE outcome reported

Study characteristics

Methods

Study design: Historically controlled trial

Study grouping:

Method: 4‐week washout period; 12‐week before‐and‐after study

Participants

Baseline Characteristics

2 mg

• n: 397

• Age (years): 55.9

• Males (n): 157

• Females (n): 240

• Total cholesterol: 250 mg/dL (6.47 mmol/L)

• LDL cholesterol: 159 mg/dL (4.10 mmol/L)

Included criteria:

Age 18‐75 years of age, gender is not limited; clinic or hospitalised patients diagnosed as hypercholesterolaemia or willing to accept for the elder brother of patients, the fasting LDL‐C ≥ 3.37 mmol/L; has not received pitavastatin in the past; signed informed consent

Excluded criteria:

Patients with pitavastatin calcium allergy; had a history of active arterial disease within 3 months such as acute coronary syndromes (i.e. unstable angina and myocardial infarction), angioplasty, angioplasty, coronary artery bypass grafting, transient ischaemic attacks, and stroke; familial cardiogenic sudden death; patients with acute heart failure; poorly controlled refractory hypertension (systolic > 160 mm Hg, diastolic > 100 mm Hg, 1 mm Hg 0.133 kPa); patients with active liver disease, severe liver and kidney dysfunction with ALT, AST and Cr values exceeding 2 times the upper limit of normal; malignancy, bed history of thyroid disease and uncontrolled acute inflammation; patients given hormones or immunosuppressants within the last 1 month; patients in the field or those who are unable to follow up because of mobility; pregnant, breastfeeding, or within 6 months of delivery

Baseline Group Characteristics: NR

Interventions

Intervention Characteristics

2 mg

Outcomes

Total cholesterol

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Lower is better

LDL cholesterol

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Lower is better

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

Judgement Comment: Controlled before‐and‐after design

Allocation concealment (selection bias)

High risk

Judgement Comment: Controlled before‐and‐after design

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Judgement Comment: Lipid parameter measurements unlikely to be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Judgement Comment: Lipid parameters were measured in a remote laboratory.

Selective reporting (reporting bias)

Low risk

Judgement Comment: LDL‐C outcome was reported.

Other bias

High risk

Judgement Comment: Kowa (Shanghai) Pharma Consulting Co. Ltd. sponsored the trial.

Incomplete outcome data (attrition bias) Total cholesterol

High risk

[(397 ‐ 295)/397]*100 = 25.7% were not included in the efficacy analysis because they were receiving lipid medications at baseline.

Incomplete outcome data (attrition bias) LDL cholesterol)

High risk

[(397 ‐ 295)/397]*100 = 25.7% were not included in the efficacy analysis because they were receiving lipid medications at baseline.

Incomplete outcome data (attrition bias) HDL cholesterol

High risk

HDL‐cholesterol was not included in the analysis because the values were expressed as medians.

Incomplete outcome data (attrition bias) Triglycerides

High risk

Triglycerides were not included in the analysis because they were expressed as medians.

Blinding of outcome assessment (detection bias)WDAEs

High risk

No comparison possible

Selective reporting (reporting bias) for WDAEs

High risk

No WDAE outcome reported

Study characteristics

Methods

Study design: Historically controlled trial

Study grouping:

Method: 4‐week washout period; 3‐month before‐and‐after study

Participants

Baseline Characteristics

2 mg

• n: 65

• Age (years): 62

• Males (n): 30

• Females (n): 35

• BMI: 24.4

• Total cholesterol: 250 mg/dL (6.465 mmol/L)

• LDL cholesterol: 165 mg/dL (4.27 mmol/L)

• HDL cholesterol: 59 mg/dL (1.53 mmol/L)

Included criteria: more than 20 years old, no chronic or acute inflammatory diseases diagnosed by clinical symptoms and/or laboratory data, no corticosteroid administration, serum creatinine concentrations ＜ 2.0 mg/dL, serum transaminase concentrations less than twice the upper limit of control ranges, and no viral hepatitis

Excluded criteria: none reported

Baseline Group Characteristics: NR

Interventions

Intervention Characteristics

2 mg

Outcomes

Total cholesterol

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Lower is better

LDL cholesterol

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Lower is better

HDL cholesterol

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Higher is better

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

Judgement Comment: Controlled before‐and‐after design

Allocation concealment (selection bias)

High risk

Judgement Comment: Controlled before‐and‐after design

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Judgement Comment: Lipid parameter measurements unlikely to be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Judgement Comment: Lipid parameters were measured in a remote laboratory.

Selective reporting (reporting bias)

Low risk

Judgement Comment: LDL‐cholesterol outcome was reported.

Other bias

High risk

Judgement Comment: This work was supported in part by a grant from the Ministry of Education, Science and Sports of Japan and "an unrestricted grant" from Kowa Pharmaceutical.

Incomplete outcome data (attrition bias) Total cholesterol

High risk

[(91 ‐ 65)/91]*100 = 28.6% were not included in the efficacy analysis.

Incomplete outcome data (attrition bias) LDL cholesterol)

High risk

[(91 ‐ 65)/91]*100 = 28.6% were not included in the efficacy analysis.

Incomplete outcome data (attrition bias) HDL cholesterol

High risk

[(91 ‐ 65)/91]*100 = 28.6% were not included in the efficacy analysis.

Incomplete outcome data (attrition bias) Triglycerides

High risk

[(91 ‐ 65)/91]*100 = 28.6% were not included in the efficacy analysis.

Blinding of outcome assessment (detection bias)WDAEs

High risk

No comparison possible

Selective reporting (reporting bias) for WDAEs

High risk

No WDAE outcome reported

Study characteristics

Methods

Study design: Randomised controlled trial

Study grouping: Parallel group

Method: No participant received lipid medications within 6 months of randomisation therefore no washout required 1 month single‐blind randomised placebo‐controlled study only the patients were blinded to the content of the tablets

Participants

Baseline Characteristics

4 mg

• n: 33

• Age (years): 60

• Males (n): 25

• Females (n): 8

• BMI: 25.5

• Total cholesterol: 240 mg/dL (6.21 mmol/L)

• LDL cholesterol: 164 mg/dL (4.24 mmol/L)

• HDL cholesterol: 43 mg/dL (1.11 mmol/L)

• Triglycerides: 165 mg/dL (1.86 mmol/L)

Placebo

• n: 32

• Age (years): 59

• Males (n): 23

• Females (n): 9

• BMI: 25.9

• Total cholesterol: 238 mg/dL (6.15 mmol/L)

• LDL cholesterol: 156 mg/dL (4.03 mmol/L)

• HDL cholesterol: 42 mg/dL (1.09 mmol/L)

• Triglycerides: 163 mg/dL (1.84 mmol/L)

Overall

• n: 65

• Age (years): 59.5

• Males (n): 48

• Females (n): 17

• BMI: 25.7

Included criteria: The study enroled 65 consecutive patients with ACS, the presence of carotid plaque [intima‐media thickness (IMT) ≥ 1.1 mm], and hypercholesterolaemia (260 > total cholesterol levels ≥ 220 mg/dL). ACS was diagnosed by the presence of acute ischaemic symptoms lasting ≥ 20 minutes within 48 hours before admission to our hospital, and electrocardiographic (ECG) changes consistent with ACS. The presence of ACS was confirmed by coronary angiography in all patients. Acute myocardial infarction (AMI) was diagnosed when creatine kinase‐MB levels increased by at least 2 times the upper level of normal (3.5 ng/mL). Patients without AMI were considered to have unstable angina pectoris (u‐AP). According to these inclusion criteria, 47 patients were diagnosed as u‐AP, and 18 patients were diagnosed as AMI.

Excluded criteria: (1) use of statin or other lipid‐lowering agents during the preceding 6 months, (2) history of hepatic disease, (3) untreated endocrine disorder, (4) history of systemic inflammatory diseases, (5) infectious diseases, (6) history of hypersensitivity to statins, (7) cardiogenic shock or pulmonary oedema at admission, or (8) stroke at admission

Baseline Group Characteristics: 65 consecutive patients with ACS were randomised. Profiles of traditional risk factors, calibrated IBS values, and levels of CRP, VEGF, and TNFa were similar between the 2 treatment groups. All ACS patients took aspirin and ticlopidine orally during the follow‐up period, and other medications and invasive therapy for culprit lesions were similar in both treatment groups

Interventions

Intervention Characteristics

4 mg

Placebo

Outcomes

Total cholesterol

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Lower is better

LDL cholesterol

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Lower is better

HDL cholesterol

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Higher is better

Triglycerides

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Lower is better

WDAE

• Outcome type: Dichotomous

• Reporting: Not reported

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Judgement Comment: The ACS patients were randomly assigned using a random number table generated by a computer.

Allocation concealment (selection bias)

High risk

Judgement Comment: Single‐blind allocation concealment was not applied to the investigators.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Judgement Comment: Single‐blind (only participants); however, lipid parameter measurements unlikely to be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Judgement Comment: Lipid parameters were measured in a remote laboratory.

Selective reporting (reporting bias)

Low risk

Judgement Comment: LDL‐cholesterol outcome was reported and WDAEs were reported; all of the study participants completed the trial with no WDAEs.

Other bias

Low risk

Judgement Comment: This study was supported by Grants‐in‐Aid for (B)(2)‐15390244 and (B)‐19390209, Priority Areas (C) ‘‘Medical Genome Science 15012222’’ from the Ministry of Education, Culture, Sports, Science, and Technology, and by Health and Labor Sciences Research Grants for Comprehensive Research on Aging and Health (H15‐Choju‐012), Tokyo, Japan, government grants

Incomplete outcome data (attrition bias) Total cholesterol

Low risk

All participants were included in the efficacy analysis.

Incomplete outcome data (attrition bias) LDL cholesterol)

Low risk

All participants were included in the efficacy analysis.

Incomplete outcome data (attrition bias) HDL cholesterol

Low risk

All participants were included in the efficacy analysis.

Incomplete outcome data (attrition bias) Triglycerides

Low risk

All participants were included in the efficacy analysis.

Blinding of outcome assessment (detection bias)WDAEs

High risk

Single‐blinded trial

Selective reporting (reporting bias) for WDAEs

Low risk

WDAE outcome reported

Study characteristics

Methods

Study design: Randomised controlled trial

Study grouping: Parallel group

Method: 4‐week single‐blind placebo run‐in period; 12‐week randomised double‐blind placebo‐controlled study with evening dosing

Participants

Baseline Characteristics

1 mg

• n: 52

• Total cholesterol: 7.3 mmol/L (282 mg/dL)

• LDL cholesterol: 5.1 mmol/L (197 mg/dL)

• HDL cholesterol: 1.4 mmol/L (54 mg/dL)

• Triglycerides: 1.8 mmol/L (159 mg/dL)

2 mg

• n: 49

• Total cholesterol: 7.4 mmol/L (286 mg/dL)

• LDL cholesterol: 5.2 mmol/L (201 mg/dL)

• HDL cholesterol: 1.5 mmol/L (58 mg/dL)

• Triglycerides: 1.8 mmol/L (159 mg/dL)

4 mg

• n: 50

• Total cholesterol: 7.4 mmol/L (286 mg/dL)

• LDL cholesterol: 5.1 mmol/L (197 mg/dL)

• HDL cholesterol: 1.4 mmol/L (54 mg/dL)

• Triglycerides: 1.8 mmol/L (159 mg/dL)

8 mg

• n: 49

• Total cholesterol: 7.4 mmol/L (286 mg/dL)

• LDL cholesterol: 5.1 mmol/L (197 mg/dL)

• HDL cholesterol: 1.6 mmol/L (62 mg/dL)

• Triglycerides: 1.6 mmol/L (142 mg/dL)

Placebo

• n: 51

• Total cholesterol: 7.4 mmol/L (286 mg/dL)

• LDL cholesterol: 5.1 mmol/L (197 mg/dL)

• HDL cholesterol: 1.5 mmol/L (58 mg/dL)

• Triglycerides: 1.6 mmol/L (142 mg/dL)

Overall

• n: 251

Included criteria: 18‐75 years; females of childbearing potential to be on oral contraception of at least 3 months; and willingness to adhere to the National Cholesterol Education Program (NCEP) Step‐1 or equivalent diet. Subjects had primary hypercholesterolaemia with LDL‐cholesterol ≥ 160 mg/dL (4.13 mmol/L) but ≤ 250 mg/dL (6.46 mmol/L), and triglyceride (TG) level ≤ 300 mg/dL (3.43 mmol/L) at Visit 3.

Excluded criteria: pregnancy, or not taking oral contraception; • BMI > 30 kg/m²; • alcohol abuse; • hypersensitivity to HMG‐CoA reductase inhibitors; • use of prohibited concomitant medications; • compliance 80% during run‐in period; • diabetes or fasting serum glucose ≥ 7 mmol/L at Visit 2; • renal impairment or serum creatinine > 1.8 mg/dL or nephrotic syndrome; • uncontrolled hypertension or diastolic blood pressure (DBP) ≥ 110 mmHg or systolic blood pressure (SBP) ≥ 180 mmHg; • history of myocardial infarction, unstable angina, stroke, transient ischaemic attack (TIA), percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass graft (CABG); • NYHA class 3 or 4 congestive cardiac failure; • active liver disease or AST or alanine aminotransferase (ALT) > 2 times ULN; • muscular or neuromuscular disease or creatinine kinase (CK) > 3 times ULN without explanation; • malignancy within past 10 years; • known cataracts; • human immunodeficiency virus (HIV) infection; • severe depression or suicidal tendencies; • Type I, IIb, III, IV or V hyperlipidaemia; • familial hypercholesterolaemia or LDL‐C > 250 mg/dL at Visit 3; and • hypercholesterolaemia secondary to hypothyroidism

Baseline Group Characteristics:NR

Interventions

Intervention Characteristics

1 mg

2 mg

4 mg

8 mg

Placebo

Outcomes

Total cholesterol

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Lower is better

LDL cholesterol

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Lower is better

HDL cholesterol

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Higher is better

Triglycerides

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Lower is better

Notes

Stephen P on 22/11/2018 13:02
Included
8 mg dose: we used the adjusted mean and imputed SDs of the percentage change but adjusted means were not calculated for total cholesterol.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Judgement Comment: Method of sequence generation was not reported.

Allocation concealment (selection bias)

Low risk

Judgement Comment: A centralised randomising system was used.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Judgement Comment: Double‐blind. Study medication was blinded and investigators did not receive lipid values during treatment period until after study completion.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Judgement Comment: Lipid parameters were measured in a remote laboratory.

Selective reporting (reporting bias)

Low risk

Judgement Comment: LDL cholesterol outcome was reported.

Other bias

High risk

Judgement Comment: Trial sponsored by laboratories Negma, a pharmaceutical company in France.

Incomplete outcome data (attrition bias) Total cholesterol

Low risk

[(252 ‐ 249)/252]*100 = 1.2 % participants were not included in the efficacy analysis.

Incomplete outcome data (attrition bias) LDL cholesterol)

Low risk

[(252 ‐ 249)/252]*100 = 1.2 % participants were not included in the efficacy analysis.

Incomplete outcome data (attrition bias) HDL cholesterol

Low risk

[(252 ‐ 249)/252]*100 = 1.2 % participants were not included in the efficacy analysis.

Incomplete outcome data (attrition bias) Triglycerides

Low risk

[(252 ‐ 249)/252]*100 = 1.2 % participants were not included in the efficacy analysis.

Blinding of outcome assessment (detection bias)WDAEs

High risk

No WDAEs were reported.

Selective reporting (reporting bias) for WDAEs

High risk

No WDAE outcome reported

Study characteristics

Methods

Study design: Randomised controlled trial

Study grouping: Parallel group

Methods: 4‐week placebo washout run‐in period; 12‐week randomised double‐blind placebo‐controlled study with evening dosing

Participants

Baseline Characteristics

1 mg

• n: 49

• Total cholesterol: 281.85 mg/dL (7.29 mmol/L)

• LDL cholesterol: 177.6 mg/dL (4.59 mmol/L)

• HDL cholesterol: 50.2 mg/dL (1.30 mmol/L)

• Triglycerides: 274.3 mg/dL (3.10 mmol/L)

2 mg

• n: 50

• Total cholesterol: 281.85 mg/dL (7.29 mmol/L)

• LDL cholesterol: 177.6 mg/dL (4.59 mmol/L)

• HDL cholesterol: 50.2 mg/dL (1.30 mmol/L)

• Triglycerides: 274.3 mg/dL (3.10 mmol/L)

4 mg

• n: 48

• Total cholesterol: 289.58 mg/dL (7.49 mmol/L)

• LDL cholesterol: 181.5 mg/dL (4.69 mmol/L)

• HDL cholesterol: 54.1 mg/dL (1.40 mmol/L)

• Triglycerides: 274.3 mg/dL (3.10 mmol/L)

Placebo

• n: 50

• Total cholesterol: 281.85 mg/dL (7.29 mmol/L)

• LDL cholesterol: 181.5 mg/dL (4.69 mmol/L)

• HDL cholesterol: 46.3 mg/dL (1.20 mmol/L)

• Triglycerides: 265.5 mg/dL (3.00 mmol./L)

Overall

• n: 197

Included criteria: 18‐75 years; females of childbearing potential to be on oral contraception of at least 3 months; and willingness to adhere to the National Cholesterol Education Program (NCEP) Step‐1 or equivalent diet. Subjects had primary mixed or combined hyperlipidaemia with LDL‐C level ≥ 135 and ≤ 300 mg/dL (≥ 3.5 and ≤ 7.8 mmol/L) and TG ≥ 175 and ≤ 500 mg/dL (≥ 2.0 and ≤ 5.7 mmol/L).

Excluded criteria: pregnancy, or not taking oral contraception; • BMI > 33 kg/m²; • alcohol abuse; • hypersensitivity to HMG‐CoA reductase inhibitors; • use of prohibited concomitant medications; • compliance 80% during run in period; • diabetes or fasting serum glucose ≥ 7 mmol/L at Visit 2; • renal impairment or serum creatinine > 1.8 mg/dL or nephrotic syndrome; • uncontrolled hypertension or diastolic blood pressure (DBP) ≥110 mmHg or systolic blood pressure (SBP) ≥ 180 mmHg; • history of myocardial infarction, unstable angina, stroke, transient ischaemic attack (TIA), percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass graft (CABG); • NYHA class 3 or 4 congestive cardiac failure; • active liver disease or AST or alanine aminotransferase (ALT) > 2 times ULN; • muscular or neuromuscular disease or creatinine kinase (CK) > 3 times ULN without explanation; • malignancy within past 10 years; • known cataracts; • human immunodeficiency virus (HIV) infection; • severe depression or suicidal tendencies; • Type I, IIb, III, IV or V hyperlipidaemia; • familial hypercholesterolaemia or LDL‐C > 250 mg/dL at Visit 3; and • hypercholesterolaemia secondary to hypothyroidism

Baseline Group Characteristics:NR

Interventions

Intervention Characteristics

1 mg

2 mg

4 mg

Placebo

Outcomes

LDL cholesterol

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Lower is better

Total cholesterol

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Lower is better

HDL cholesterol

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Higher is better

Triglycerides

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Lower is better

WDAE

• Outcome type: Dichotomous

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Judgement Comment: Method of sequence generation was not reported.

Allocation concealment (selection bias)

Low risk

Judgement Comment: A centralised randomising system was used.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Judgement Comment: double‐blind. Study medication was blinded and investigators did not receive lipid values during treatment period until after study completion.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Judgement Comment: Lipid parameters were measured in a remote laboratory.

Selective reporting (reporting bias)

Low risk

Judgement Comment: LDL cholesterol outcome was reported.

Other bias

High risk

Judgement Comment: The study was sponsored by Laboratories Negma, a pharmaceutical company in France.

Incomplete outcome data (attrition bias) Total cholesterol

Low risk

[(261 ‐ 251)/261)]*100 = 3.8% participants were not included in the efficacy analysis.

Incomplete outcome data (attrition bias) LDL cholesterol)

Low risk

[(261 ‐ 251)/261)]*100 = 3.8% participants were not included in the efficacy analysis.

Incomplete outcome data (attrition bias) HDL cholesterol

Low risk

[(261 ‐ 251)/261)]*100 = 3.8% participants were not included in the efficacy analysis.

Incomplete outcome data (attrition bias) Triglycerides

Low risk

[(261 ‐ 251)/261)]*100 = 3.8% participants were not included in the efficacy analysis.

Blinding of outcome assessment (detection bias)WDAEs

Unclear risk

Blinding method was not described.

Selective reporting (reporting bias) for WDAEs

Low risk

WDAE outcome reported

Study characteristics

Methods

Study design: Randomised controlled trial

Study grouping: Parallel group

Methods: 6 to 8‐week dietary washout period; 8‐week randomised double‐blind placebo‐controlled trial

Participants

Baseline Characteristics

none reported

Included criteria: participants 18 to 80 years with plasma mean LDL‐C levels at two consecutive qualifying visits ≥ 130 mg/dL and ≤ 220 mg/dL, and triglycerides ≤ 400 mg/dL

Excluded criteria: pregnancy, or not taking oral contraception; • BMI > 30 kg/m²; • alcohol abuse; • hypersensitivity to HMG‐CoA reductase inhibitors; • use of prohibited concomitant medications; • compliance < 80% during run‐in period; • diabetes or fasting serum glucose ≥ 7 mmol/L at Visit 2; • renal impairment or serum creatinine > 1.8 mg/dL or nephrotic syndrome; • uncontrolled hypertension or diastolic blood pressure (DBP) ≥ 110 mmHg or systolic blood pressure (SBP) ≥ 180 mmHg; • history of myocardial infarction, unstable angina, stroke, transient ischaemic attack (TIA), percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass graft (CABG); • NYHA class 3 or 4 congestive cardiac failure; • active liver disease or AST or alanine aminotransferase (ALT) > 2 times ULN; • muscular or neuromuscular disease or creatinine kinase (CK) > 3 times ULN without explanation; • malignancy within past 10 years; • known cataracts; • human immunodeficiency virus (HIV) infection; • severe depression or suicidal tendencies; • Type I, IIb, III, IV or V hyperlipidaemia; • familial hypercholesterolaemia or LDL‐C > 250 mg/dL at Visit 3; and • hypercholesterolaemia secondary to hypothyroidism

Baseline Group Characteristics:NR

Interventions

Intervention Characteristics

8 mg

16 mg

Placebo

Outcomes

LDL cholesterol

• Outcome type: Continuous

• Unit of measure: Percentage change from baseline

• Direction: Lower is better

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Judgement Comment: Random sequence generation method not reported

Allocation concealment (selection bias)

Unclear risk

Judgement Comment: Allocation concealment not reported

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Judgement Comment: Double‐blind treatment lipid parameter measurements unlikely to be influenced by lack of proper blinding

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Judgement Comment: Lipid parameters were measured in a remote laboratory.

Selective reporting (reporting bias)

Low risk

Judgement Comment: LDL‐cholesterol outcome was reported.

Other bias

High risk

Judgement Comment: Sankyo Pharma sponsored the trial.

Incomplete outcome data (attrition bias) Total cholesterol

High risk

No total cholesterol data reported

Incomplete outcome data (attrition bias) LDL cholesterol)

Low risk

[(54 ‐ 53)/54]*100 = 1.9% participants for placebo group

[(107 ‐ 103)/107]*100 = 3.7% participants for the pitavastatin 8 mg/day group

[(107 ‐ 103)/107]*100 = 3.7% participants for the pitavastatin 16 mg/day group

Incomplete outcome data (attrition bias) HDL cholesterol

High risk

No HDL cholesterol data reported

Incomplete outcome data (attrition bias) Triglycerides

High risk

No triglyceride data reported

Blinding of outcome assessment (detection bias)WDAEs

High risk

No WDAE data reported

Selective reporting (reporting bias) for WDAEs

High risk

No WDAE outcome reported

Study characteristics

Methods

Study design: Historically controlled trial

Study grouping:

Method: 4‐8 week placebo washout period; 8‐week before‐and‐after study with evening dosing

Participants

Baseline Characteristics

2 mg

• n: 25

• Age (years): 53

• Males (n): 11

• Females (n): 14

• Total cholesterol: 340 mg/dL (8.79 mmol/L)

• LDL cholesterol: 267 mg/dL (6.90 mmol/L)

• HDL cholesterol: 48 mg/dL (1.24 mmol/L)

• BMI: 24.6