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.

Amgen Thousand Oaks California

Cardiology Department Cordoba Hospital Cordoba Argentina

Center of Preventive Cardiology 3rd Department Internal Medicine University General Hospital and 1st Medical Faculty Prague Czech Republic

CIBER Fisiopatología de la Obesidad y Nutrición Cordoba Spain

Ciccarone Center for the Prevention of Cardiovascular Disease Division of Cardiology Johns Hopkins University School of Medicine Baltimore Maryland

Department of Cardiology National Heart Hospital Sofia Bulgaria

Deputy Editor

Folkhälsan Research Center University of Helsinki Helsinki Finland

Harvard Medical School Boston Massachusetts

International Centre for Circulatory Health National Heart and Lung Institute Imperial College London London England

Lipids and Atherosclerosis Unit Maimonides Biomedical Research Institute of Cordoba Reina Sofía University Hospital University of Cordoba Cordoba Spain

Metabolic and Atherosclerosis Research Center Cincinnati Ohio

Oslo University Hospital Ullevål and Medical Faculty University of Oslo Oslo Norway

Sydney Medical School National Health and Medical Research Council Clinical Trials Centre University of Sydney Sydney Australia

Thrombolysis in Myocardial Infarction Study Group Division of Cardiovascular Medicine Brigham and Women's Hospital Boston Massachusetts

JAMA Cardiol. 2018 Aug 1;3(8):754-755. doi: 10.1001/jamacardio.2018.1575. PubMed

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Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18(6):499-502. PubMed

Lloyd-Jones DM, Morris PB, Ballantyne CM, et al. . 2017 focused update of the 2016 ACC expert consensus decision pathway on the role of non-statin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk: a report of the American College of Cardiology Task Force. J Am Coll Cardiol. 2017;70(14):1785-1822. PubMed

Catapano AL, Graham I, De Backer G, et al. ; ESC Scientific Document Group . 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias. Eur Heart J. 2016;37(39):2999-3058. PubMed

Orringer CE, Jacobson TA, Saseen JJ, et al. . Update on the use of PCSK9 inhibitors in adults: Recommendations from an Expert Panel of the National Lipid Association. J Clin Lipidol. 2017;11(4):880-890. PubMed

Martin SS, Blaha MJ, Elshazly MB, et al. . Friedewald-estimated versus directly measured low-density lipoprotein cholesterol and treatment implications. J Am Coll Cardiol. 2013;62(8):732-739. PubMed

Miller WG, Myers GL, Sakurabayashi I, et al. . Seven direct methods for measuring HDL and LDL cholesterol compared with ultracentrifugation reference measurement procedures. Clin Chem. 2010;56(6):977-986. PubMed PMC

Miller WG, Waymack PP, Anderson FP, Ethridge SF, Jayne EC. Performance of four homogeneous direct methods for LDL-cholesterol. Clin Chem. 2002;48(3):489-498. PubMed

Martin SS, Blaha MJ, Elshazly MB, et al. . Comparison of a novel method vs the Friedewald equation for estimating low-density lipoprotein cholesterol levels from the standard lipid profile. JAMA. 2013;310(19):2061-2068. PubMed PMC

Meeusen JW, Lueke AJ, Jaffe AS, Saenger AK. Validation of a proposed novel equation for estimating LDL cholesterol. Clin Chem. 2014;60(12):1519-1523. PubMed

Lee J, Jang S, Son H. Validation of the Martin method for estimating low-density lipoprotein cholesterol levels in Korean adults: Findings from the Korea national health and nutrition examination survey, 2009-2011. PLoS One. 2016;11(1):e0148147. PubMed PMC

Chaen H, Kinchiku S, Miyata M, et al. . Validity of a novel method for estimation of low-density lipoprotein cholesterol levels in diabetic patients. J Atheroscler Thromb. 2016;23(12):1355-1364. PubMed PMC

Kang M, Kim J, Lee SY, Kim K, Yoon J, Ki H. Martin’s equation as the most suitable method for estimation of low-density lipoprotein cholesterol levels in Korean adults. Korean J Fam Med. 2017;38(5):263-269. PubMed PMC

Sathiyakumar V, Park J, Golozar A, et al. . Fasting versus nonfasting and low-density lipoprotein cholesterol accuracy. Circulation. 2018;137(1):10-19. PubMed

Sabatine MS, Giugliano RP, Keech AC, et al. ; FOURIER Steering Committee and Investigators . Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376(18):1713-1722. PubMed

Giugliano RP, Pedersen TR, Park JG, et al. ; FOURIER Investigators . Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial. Lancet. 2017;390(10106):1962-1971. PubMed

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ClinicalTrials.gov
NCT01764633