ARTICLE: Comparison of Low-density Lipoprotein Cholesterol Assessment by Martin/Hopkins Estimation, Friedewald Estimation, and Preparative Ultracentrifugation Insights From the FOURIER Trial

AUTHORS: 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

JOURNAL: JAMA Cardiol. 2018 Jun 13. doi: 10.1001/jamacardio.2018.1533. [Epub ahead of print]


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 estimationmore 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.

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