Comparison of low-density lipoprotein cholesterol assessment by Martin/Hopkins estimation, friedewald estimation, and preparative ultracentrifugation insights from the FOURIER trial

Seth S. Martin, Robert P. Giugliano, Sabina A. Murphy, Scott M. Wasserman, Evan A. Stein, Richard Češka, José López-Miranda, Borislav Georgiev, Alberto J. Lorenzatti, Matti J. Tikkanen, Peter S. Sever, Anthony C. Keech, Terje R. Pedersen, Marc S. Sabatine

Research output: Contribution to journalArticlepeer-review

Abstract

IMPORTANCE Recent studies have shown that Friedewald underestimates low-density lipoprotein cholesterol (LDL-C) at lower levels, which could result in undertreatment of high-risk patients. A novel method (Martin/Hopkins) using a patient-specific conversion factor provides more accurate LDL-C levels. However, this method has not been tested in proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor–treated patients. OBJECTIVE To investigate accuracy of 2 different methods for estimating LDL-C levels (Martin/Hopkins and Friedewald) compared with gold standard preparative ultracentrifugation (PUC) in patients with low LDL-C levels in the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk (FOURIER) trial. DESIGN, SETTING, AND PARTICIPANTS The FOURIER trial was a randomized clinical trial of evolocumab vs placebo added to statin therapy in 27 564 patients with stable atherosclerotic cardiovascular disease. The patients’ LDL-C levels were assessed at baseline, 4 weeks, 12 weeks, 24 weeks, and every 24 weeks thereafter, and measured directly by PUC when the level was less than 40 mg/dL per the Friedewald method (calculated as non–HDL-C level − triglycerides/5). In the Martin/Hopkins method, patient-specific ratios of triglycerides to very low-density lipoprotein cholesterol (VLDL-C) ratios were determined and used to estimate VLDL-C, which was subtracted from the non–HDL-C level to obtain the LDL-C level. MAIN OUTCOMES AND MEASURES Low-density lipoprotein cholesterol calculated by the Friedewald and Martin/Hopkins methods, with PUC as the reference method. RESULTS For this analysis, the mean (SD) age was 62.7 (9.0) years; 2885 of the 12 742 patients were women (22.6%). A total of 56 624 observations from 12 742 patients had Friedewald, Martin/Hopkins, and PUC LDL-C measurements. The median difference from PUC LDL-C levels for Martin/Hopkins LDL-C levels was −2 mg/dL (interquartile range [IQR], −4 to 1 mg/dL) and for Friedewald LDL-C levels was −4 mg/dL (IQR, −8 to −1 mg/dL; P < .001). Overall, 22.9% of Martin/Hopkins LDL-C values were more than 5 mg/dL different than PUC values, and 2.6% were more than 10 mg/dL different than PUC levels. These were significantly less than respective proportions with Friedewald estimation (40.1% and 13.3%; P < .001), mainly because of underestimation by the Friedewald method. The correlation with PUC LDL-C was significantly higher for Martin/Hopkins vs Friedewald (ρ, 0.918 [95% CI 0.916-0.919] vs ρ, 0.867 [0.865-0.869], P < .001). CONCLUSIONS AND RELEVANCE In patients achieving low LDL-C with PCSK9 inhibition, the Martin/Hopkins method for LDL-C estimation more closely approximates gold standard PUC than Friedewald estimation does. The Martin/Hopkins method may prevent undertreatment because of LDL-C underestimation by the Friedewald method.

Original languageEnglish (US)
Pages (from-to)749-753
Number of pages5
JournalJAMA cardiology
Volume3
Issue number8
DOIs
StatePublished - Aug 2018

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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