Original Investigation
Visit-to-Visit Low-Density Lipoprotein Cholesterol Variability and Risk of Cardiovascular Outcomes: Insights From the TNT Trial

This work was presented in part at the 2012 Annual Scientific Session of the European Society of Cardiology, Munich, Germany.
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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.

Objectives

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.

Key Words

cardiovascular outcomes
LDL cholesterol
variability

Abbreviations and Acronyms

ASV
average successive variability
CAD
coronary artery disease
CV
coefficient of variation
HR
hazard ratio
LDL-C
low-density lipoprotein cholesterol
MI
myocardial infarction
VIM
variation independent of mean

Cited by (0)

The TNT study was sponsored by Pfizer Inc. Dr. Bangalore has been an ad-hoc consultant to Daiichi-Sankyo, Pfizer, and Boehringer Ingelheim. Drs. Breazna, Wun, and DeMicco are employees of Pfizer. Dr. Messerli has been an ad-hoc consultant to Abbott, Novartis, Pfizer, Bayer, Forest, Takeda, and Daiichi-Sankyo; and he has received research grants from Novartis and Boehringer Ingelheim.

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