Monitoring Cholesterol Levels: Measurement Error or True Change?

6 May 2008 | Volume 148 Issue 9 | Pages 656-661

Background: Cholesterol level monitoring is a common clinical activity, but the optimal monitoring interval is unknown and practice varies.

Objective: To estimate, in patients receiving cholesterol-lowering medication, the variation in initial response to treatment, the long-term drift from initial response, and the detectability of long-term changes in on-treatment cholesterol level ("signal") given short-term, within-person variation ("noise").

Design: Analysis of cholesterol measurement data in the LIPID (Long-Term Intervention with Pravastatin in Ischaemic Disease) study.

Setting: Randomized, placebo-controlled trial in Australia and New Zealand (June 1990 to May 1997).

Patients: 9014 patients with past coronary heart disease who were randomly assigned to receive pravastatin or placebo.

Measurements: Serial cholesterol concentrations at randomization, 6 months, and 12 months, and then annually to 5 years.

Results: Both the placebo and pravastatin groups showed small increases in within-person variability over time. The estimated within-person SD increased from 0.40 mmol/L (15 mg/dL) (coefficient of variation, 7%) to 0.60 mmol/L (23 mg/dL) (coefficient of variation, 11%), but it took almost 4 years for the long-term variation to exceed the short-term variation. This slow increase in variation and the modest increase in mean cholesterol level, about 2% per year, suggest that most of the variation in the study is due to short-term biological and analytic variability. Our calculations suggest that, for patients with levels that are 0.5 mmol/L or more (19 mg/dL) under target, monitoring is likely to detect many more false-positive results than true-positive results for at least the first 3 years after treatment has commenced.

Limitations: Patients may respond differently to agents other than pravastatin. Future values for nonadherent patients were imputed.

Conclusion: The signal–noise ratio in cholesterol level monitoring is weak. The signal of a small increase in cholesterol level is difficult to detect against the background of a short-term variability of 7%. In annual rechecks in adherent patients, many apparent increases in cholesterol level may be false positive. Independent of the office visit schedule, the interval for monitoring patients who are receiving stable cholesterol-lowering treatment could be lengthened.

Editors' Notes Context What is the optimal monitoring interval for patients taking cholesterol-lowering medication? Contribution This analysis of data from a trial that compared pravastatin with placebo in patients with coronary disease found that the signal–noise ratio in cholesterol monitoring was weak. Short-term variability of measurement was about –0.80 to 0.80 mmol/L (–31 to 31 mg/dL). Calculations suggested that frequent follow-up of patients with values 0.5 mmol/L (19 mg/dL) or more under target detected many more false-positive results than truly elevated cholesterol values. Implication Consider testing adherent patients with well-controlled cholesterol levels every 3 to 5 years rather than every few months or annually. —The Editors

 

Author and Article Information

From the University of Oxford, Oxford, United Kingdom; University of Sydney, Sydney, Australia; and Monash University, Melbourne, Australia.

Acknowledgment: The authors thank Tim James for local cholesterol level testing data; Katy Bell, Jorgen Hilden, Martin Turner, Andrew Hayen, and members of the LIPID management committee—David Sullivan, Harvey White, Paul Nestel, and David Colquhoun—for helpful comments; and Rhana Pike for editorial work.

Potential Financial Conflicts of Interest: None disclosed.

Reproducible Research Statement: Study protocol: The original 2-page proposal is available from Dr. Glasziou (e-mail, paul.glasziou{at}dphpc.ox.ac.uk). Statistical code: Available from Dr. Heritier (e-mail, sheritier{at}george.org.au). Data set: Not available.

Requests for Single Reprints: Paul P. Glasziou, MBBS, PhD, Centre for Evidence-Based Medicine, Department of Primary Health Care, University of Oxford, Old Road Campus, Oxford OX3 7LF, United Kingdom; e-mail, paul.glasziou{at}dphpc.ox.ac.uk.

Current Author Addresses: Dr. Glasziou: Centre for Evidence-Based Medicine, Department of Primary Health Care, University of Oxford, Old Road Campus, Oxford OX3 7LF, United Kingdom.

Dr. Irwig: Screening and Test Evaluation Program, School of Public Health, University of Sydney, Sydney, Australia.

Drs. Heritier and Simes: NHMRC Clinical Trials Centre, University of Sydney, Sydney, Australia.

Dr. Tonkin: Department of Epidemiology & Preventive Medicine, Monash University, Melbourne, Australia.

Author Contributions: Conception and design: P.P. Glasziou, L. Irwig.

Analysis and interpretation of the data: P.P. Glasziou, L. Irwig, S. Heritier, R.J. Simes, A. Tonkin.

Drafting of the article: P.P. Glasziou, L. Irwig, S. Heritier.

Critical revision of the article for important intellectual content: P.P. Glasziou, L. Irwig, R.J. Simes, A. Tonkin.

Final approval of the article: P.P. Glasziou, L. Irwig, S. Heritier, R.J. Simes, A. Tonkin.

Statistical expertise: P.P. Glasziou, S. Heritier.

Obtaining of funding: P.P. Glasziou, A. Tonkin.

Administrative, technical, or logistic support: R.J. Simes.

Collection and assembly of data: P.P. Glasziou.