title: Visit-to-visit low-density lipoprotein cholesterol variability and risk of cardiovascular outcomes: insights from the TNT trial.
abstract: BACKGROUND
  Studies demonstrate that lowering low-density lipoprotein cholesterol (LDL-C) using a statin is associated with significant reduction in cardiovascular events. Whether visit-to-visit variability in LDL-C levels affects cardiovascular outcomes is unknown.
  
  
  OBJECTIVE
  This study sought to evaluate the role of visit-to-visit variability in LDL-C levels on cardiovascular outcomes.
  
  
  METHODS
  We evaluated patients with coronary artery disease and LDL-C <130 mg/dl enrolled in the TNT (Treating to New Targets) trial, randomly assigned to receive atorvastatin 80 mg/day versus 10 mg/day and with at least one post-baseline measurement of LDL-C. Visit-to-visit LDL-C variability was evaluated from 3 months into random assignment through the use of various measurements of LDL-C variability: SD, average successive variability (ASV), coefficient of variation, and variation independent of mean, with the first 2 measurements used as the primary measurements. Primary outcome was any coronary event, and secondary outcomes were any cardiovascular event, death, myocardial infarction, or stroke.
  
  
  RESULTS
  Among 9,572 patients, SD and ASV were significantly lower with atorvastatin 80 mg/day versus 10 mg/day (SD: 12.03 ± 9.70 vs. 12.52 ± 7.43; p = 0.005; ASV: 12.84 ± 10.48 vs. 13.76 ± 8.69; p < 0.0001). In the adjusted model, each 1-SD increase in LDL-C variability (by ASV) increased the risk of any coronary event by 16% (hazard ratio [HR]: 1.16; 95% confidence interval [CI]: 1.10 to 1.23; p < 0.0001), any cardiovascular event by 11% (HR: 1.11; 95% CI: 1.07 to 1.15; p < 0.0001), death by 23% (HR: 1.23; 95% CI: 1.14 to 1.34; p < 0.0001), myocardial infarction by 10% (HR: 1.10; 95% CI: 1.02 to 1.19; p = 0.02), and stroke by 17% (HR: 1.17; 95% CI: 1.04 to 1.31; p = 0.01), independent of treatment effect and achieved LDL-C levels. Results were largely consistent when adjusted for medication adherence.
  
  
  CONCLUSIONS
  In subjects with coronary artery disease, visit-to-visit LDL-C variability is an independent predictor of cardiovascular events.
authors.affiliation: Division of Cardiology, New York University School of Medicine, New York, New York. Electronic address: sripalbangalore@gmail.com.
authors.forename: Sripal
authors.initials: S
authors.lastname: Bangalore
authors.affiliation: Pfizer, New York, New York.
authors.forename: Andrei
authors.initials: A
authors.lastname: Breazna
authors.affiliation: Pfizer, New York, New York.
authors.forename: David A
authors.initials: DA
authors.lastname: DeMicco
authors.affiliation: Pfizer, New York, New York.
authors.forename: Chuan-Chuan
authors.initials: CC
authors.lastname: Wun
authors.affiliation: Division of Cardiology, St. Luke's-Roosevelt Hospital, Mount Sinai School of Medicine, New York, New York.
authors.forename: Franz H
authors.initials: FH
authors.lastname: Messerli
mesh_terms: D000328:Adult; D000368:Aged; D000789:Angina, Unstable / Q000453:epidemiology; D000069059:Atorvastatin; D008078:Cholesterol, LDL / Q000097:blood*; D003324:Coronary Artery Disease / Q000097:blood* / Q000188:drug therapy / Q000401:mortality*; D005500:Follow-Up Studies; D006323:Heart Arrest / Q000453:epidemiology; D006538:Heptanoic Acids / Q000008:administration & dosage; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage; D008875:Middle Aged; D009203:Myocardial Infarction / Q000453:epidemiology*; D009204:Myocardial Revascularization; D011758:Pyrroles / Q000008:administration & dosage; D020521:Stroke / Q000453:epidemiology*
chemical_list: D008078:Cholesterol, LDL; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D000069059:Atorvastatin
keywords: LDL cholesterol; cardiovascular outcomes; variability