title: Relationship between lipid levels and clinical outcomes in the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) Trial: to what extent is the reduction in coronary events with pravastatin explained by on-study lipid levels?
abstract: BACKGROUND
  The Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) trial showed that pravastatin significantly reduced mortality and coronary heart disease (CHD) events in 9014 patients with known CHD and total cholesterol 4.0 to 7.0 mmol/L at baseline. Secondary objectives included assessment of CHD event reduction according to lipid levels.
  
  
  RESULTS
  We investigated the relationships of baseline and on-study lipids with subsequent CHD events in separate Cox models. Treatment effect on CHD event reduction was examined by baseline lipids and after adjustment for on-study lipid levels. Baseline lipids were significant predictors of CHD events. The adjusted relative risk per mmol/L (on placebo) was 1.24 (P=0.004) for total cholesterol, 1.28 (P=0.002) for low-density lipoprotein cholesterol, and 0.52 (P=0.004) for high-density lipoprotein cholesterol. Apolipoproteins A1 and B were strong predictors (each P=0.001). Pravastatin reduced the risk of the composite outcome of fatal CHD or nonfatal myocardial infarction by 24% (95% confidence interval [CI], 15% to 32%) and the expanded end point of fatal CHD, nonfatal myocardial infarction, unstable angina, or coronary revascularization by 17% (95% CI, 10% to 24%). Similar relative effects were observed for different categories of baseline lipids. The proportion of treatment effect explained by on-study lipid levels was 67% (95% CI, 27% to 106%) for the composite and 97% (95% CI, 49% to 145%) for the expanded end point. The most important lipids associated with event reduction were apolipoprotein B, low-density lipoprotein cholesterol, and the combination of total and high-density lipoprotein cholesterol.
  
  
  CONCLUSIONS
  Changes in lipid levels can explain all or most of the observed benefit of pravastatin. Some treatment effect may also be mediated through nonlipid changes.
authors.affiliation: National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Australia. enquiry@ctc.usyd.edu.au
authors.forename: R John
authors.initials: RJ
authors.lastname: Simes
authors.forename: Ian C
authors.initials: IC
authors.lastname: Marschner
authors.forename: David
authors.initials: D
authors.lastname: Hunt
authors.forename: David
authors.initials: D
authors.lastname: Colquhoun
authors.forename: David
authors.initials: D
authors.lastname: Sullivan
authors.forename: Ralph A H
authors.initials: RA
authors.lastname: Stewart
authors.forename: Wendy
authors.initials: W
authors.lastname: Hague
authors.forename: Anthony
authors.initials: A
authors.lastname: Keech
authors.forename: Peter
authors.initials: P
authors.lastname: Thompson
authors.forename: Harvey
authors.initials: H
authors.lastname: White
authors.forename: John
authors.initials: J
authors.lastname: Shaw
authors.forename: Andrew
authors.initials: A
authors.lastname: Tonkin
mesh_terms: D000328:Adult; D000368:Aged; D000789:Angina, Unstable / Q000097:blood* / Q000188:drug therapy; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D016632:Apolipoprotein A-I / Q000097:blood; D001055:Apolipoproteins B / Q000097:blood; D002784:Cholesterol / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D003327:Coronary Disease / Q000517:prevention & control; D023381:Endpoint Determination; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D008055:Lipids / Q000097:blood*; D008875:Middle Aged; D009203:Myocardial Infarction / Q000097:blood* / Q000188:drug therapy; D017035:Pravastatin / Q000627:therapeutic use; D016016:Proportional Hazards Models; D016032:Randomized Controlled Trials as Topic / Q000706:statistics & numerical data; D012306:Risk; D018570:Risk Assessment; D012307:Risk Factors; D013995:Time; D016896:Treatment Outcome; D014280:Triglycerides / Q000097:blood
chemical_list: D000924:Anticholesteremic Agents; D016632:Apolipoprotein A-I; D001055:Apolipoproteins B; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids; D014280:Triglycerides; D002784:Cholesterol; D017035:Pravastatin