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. 2016 Nov 26;2016(11):CD009462. doi: 10.1002/14651858.CD009462.pub2

Hunninghake 1990.

Methods Study design: randomised, double‐blind, parallel, placebo‐controlled study
 Setting/location: six lipid treatment centres. Country: USA
 Period of study: not reported
 Unit of randomisation: participants
 Unit of analysis: participants
Participants Inclusion criteria:

  • Primary hypercholesterolaemia

  • Age 20‐72 years

  • LDL‐C concentration ≥ 85th percentile for age and sex despite dietary intervention and a triglyceride concentration ≤ 250 mg/dL


Exclusion criteria:

  • Premenopausal women (unless surgically sterilised)

  • Insulin‐dependent diabetes mellitus

  • Non‐insulin‐dependent diabetes mellitus with fasting blood glucose > 140 mg/dL

  • Blood pressure > 160/100 mm Hg

  • Myocardial infarction within 6 months

  • Severe or unstable angina pectoris or uncompensated heart failure

  • Significant renal or hepatic disease

  • Excesive obesity (> 40% above ideal body weight)

  • Consumption of more than 10 alcoholic drinks per week

  • Participants with hypercholesterolaemia types III, IV or V


Enrolled: 228 participants
Randomised: 196 participants (not reported data by group)
Withdrawals: 8 participants: 2 for personal reasons (1 morning and 1 placebo group), 2 for open heart surgery (1 evening and 1 twice‐daily group), 1 because of chronic lymphocytic leukaemia (evening group), 1 was lost to follow‐up (evening group), 1 was withdrawn because of erroneous randomisation and 1 due to gastrointestinal discomfort (placebo group)
Participants assessed (efficacy): 184 participants (M‐DG: n = 48, E‐DG: n = 43, PG: n = 46 and twice‐daily group: n = 47). 12 participants were excluded from the efficacy analysis: 9 deviation from entrance criteria and 3 for change in concomitant medication potentially affecting lipid metabolism (page 222 trial report)
Participants assessed (safety analysis): 196 participants
Definition of hyperlipidaemia: fasting LDL‐C concentration ≥ 85th percentile for age and sex than North American populations and a Trygliceride concentration ≤ 250 mg/dL
Baseline characteristics:
Age (years) (mean): M‐DG: 53.3, E‐DG: 54, PG: 53.5 and twice‐daily group: 52.6
Total cholesterol (TC) (mg/dL) (mean (SD)): M‐DG: 320.2 (10.1), E‐DG: 320.6 (11.2), PG: 326 (9.3) and twice‐daily group: 322.9 (10.1)
LDL‐C (mg/dL) (mean): M‐DG: 242.7, E‐DG: 244.6, PG: 249.8 and twice‐daily group: 244.7.
HDL‐C (mg/dL) (mean (SD)): M‐DG: 44.5 (1.6), E‐DG: 44.5 (1.9), PG: 46.4 (1.6) and twice‐daily group: 44.1 (1.6)
T riglycerides (mg/dL) (mean (SD)): M‐DG: 55.7 (3.1), E‐DG: 55.3 (4.6), PG: 55.3 (3.5) and twice‐daily group: 59.9 (3.5)
Interventions Type of interventions: morning vs evening vs twice‐daily doses of pravastatin
 M‐DG: 40 mg daily dose of pravastatin in the morning
 E‐DG: 40 mg daily dose of pravastatin in the evening
 Twice‐daily group (TDG): 20 mg twice daily (am + pm) of pravastatin
Placebo group (PG): placebo
Duration of intervention: 14 weeks (figure 1 trial report)
Pre‐randomisation period: 6 weeks
Treatment phase: 8 weeks
Outcomes Change in lipid levels: TC, LDL‐C, HDL‐C and triglycerides levels (mg/dL)
Drug compliance (consumption)
Safety outcomes
Notes  
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk No information provided
Allocation concealment (selection bias) Unclear risk No information provided
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Quote: "Pravastatin and placebo were supplied as identical‐appearing tablets in blister cards. To maintain double‐blind conditions during the treatment phase, drug supplies were packaged so each patient received the same number of tablets each day." (page 221 trial report)
Blinding of outcome assessment (detection bias) 
 All outcomes Low risk Quote: "Blood chemistry analysis was performed centrally at the university of Cincinnati" (page 221 trial report)
Incomplete outcome data (attrition bias) 
 All outcomes Low risk Quote: "228 patients were enrolled, of which 196 qualified and were randomised to receive pravastatin or placebo. A total of 188 patients completed 8 weeks of double‐blind treatment." (8/196; 4.1%)
"The included population (evaluated for efficacy) comprised 184 patients" (page 222 trial report)
Selective reporting (reporting bias) High risk Not reported the number of analysed patients in each arm
There is no protocol available
Other bias Unclear risk Insufficient information to assess whether an important risk of bias existed