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Comparative Study
. 2018 Aug 1;3(8):749-753.
doi: 10.1001/jamacardio.2018.1533.

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

Seth S Martin  1 , Robert P Giugliano  2   3 , Sabina A Murphy  2   3 , Scott M Wasserman  4 , Evan A Stein  5 , Richard Ceška  6 , José López-Miranda  7   8 , Borislav Georgiev  9 , Alberto J Lorenzatti  10 , Matti J Tikkanen  11 , Peter S Sever  12 , Anthony C Keech  13 , Terje R Pedersen  14 , Marc S Sabatine  2   3   15
Affiliations
Comparative Study

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

Seth S Martin et al. JAMA Cardiol. .

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.

Trial registration: ClinicalTrials.gov Identifier: NCT01764633.

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Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Martin reports receiving personal fees for serving on scientific advisory boards for Amgen, Sanofi/Regeneron, Quest Diagnostics, and Akcea Therapeutics, as well as grants and research support from the PJ Schafer Cardiovascular Research Fund, the David and June Trone Family Foundation, American Heart Association, Aetna Foundation, Maryland Innovation Initiative, Nokia, Google, and Apple outside the submitted work; in addition, he reports having patent applications pending. Dr Giugliano reports receiving grants from Amgen during the conduct of the study; grants and personal fees from Merck; and personal fees from American College of Cardiology, Bristol-Myers Squibb, CVS Caremark, Daiichi Sankyo, GlaxoSmithKline, Pfizer, and Sanofi outside the submitted work. Dr Murphy reports receiving grants from Abbott Laboratories, Amarin, Amgen, AstraZeneca, Critical Diagnostics, Daiichi Sankyo, Eisai, GlaxoSmithKline, Intarcia Therapeutics, Merck and Co, Roche Diagnostics, Takeda, Gilead, Poxel, Novartis, MedImmune, Janssen Research Development, and Genzyme outside the submitted work. Dr Wasserman reports receiving support from Amgen, Inc during the conduct of the study, as well as other support from Amgen, Inc outside the submitted work; in addition, he has patent applications pending. Dr Stein reports receiving consultant and expert witness fees from AstraZeneca regarding statins. Dr López Miranda reports having served as a Country Coordinator and Member of the FOURIER Study Steering Committee and received research grant support from its sponsor, Amgen, as well as personal fees and nonfinancial support from Sanofi, personal fees from MSD, and personal fees from Laboratories Dr Esteve. Dr Georgiev reports receiving personal fees from Amgen during the conduct of the study, as well as personal fees from Pfizer, Sanofi, and Novartis outside the submitted work. Dr Lorenzatti reports having served as a country coordinator and member of the FOURIER Study Steering Committee and received research grant support from its sponsor, Amgen. Dr Tikkanen reports serving on advisory boards (Amgen and Aegerion), acting as a consultant (Amgen), and receiving speaker’s fees (Amgen and Aegerion). Dr Sever reports receiving grants and personal fees from Amgen and Pfizer during the conduct of the study and outside the submitted work. Dr Keech reports receiving grants and personal fees from Abbott and Mylan and personal fees from Amgen Inc, AstraZeneca, and Pfizer outside the submitted work. Dr Pedersen reports receiving grants and personal fees from Amgen during the conduct of the study and personal fees from Amgen, Sanofi, Boehringer Ingelheim, The Medicines Company, and Merck and Co outside the submitted work. Dr Sabatine reports receiving grants from Abbott Laboratories, Clinical Diagnostics, Daiichi Sankyo, Gilead, GlaxoSmithKline, Roche Diagnostics, Takeda, Novartis, Poxel, Eisai, Genzyme, and Pfizer outside the submitted work; grants and personal fees from Amgen, AstraZeneca, Intarcia, Merck, Janssen Research Development, MedImmune, Medicines Company, and Novartis outside the submitted work; and personal fees from Alnylam, Bristol-Myers Squibb, CVS Caremark, Ionis, Cubist, Esperion, and MyoKardia outside the submitted work. No other disclosures are reported.

Figures

Figure.
Figure.. Scatterplots of Estimated Low-Density Lipoprotein Cholesterol (LDL-C) vs Preparative Ultracentrifugation Measured LDL-C
A line of unity (solid line) and regression line (dashed line) are shown. Note that the study population was defined by Friedewald LDL-C estimations less than 40 mg/dL, whereas Martin/Hopkins and preparative ultracentrifugation values extended to higher levels up to 75 mg/dL. LDL-C indicates low-density lipoprotein cholesterol.
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