martin/hopkins estimation, friedewald and beta- quantification … fourier nla... · 2018-07-06 ·...

Abstract

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Martin/Hopkins Estimation, Friedewald and Beta-Quantification of LDL-C in Patients in FOURIER

Seth S. Martin, M.D., M.H.S.,1 Robert P. Giugliano, M.D., S.M.,2 Sabina A. Murphy, M.P.H.,2 Scott M. Wasserman, M.D.,3 Peter S. Sever, Ph.D., F.R.C.P.,4 Anthony C. Keech, M.D.,5 Terje R. Pedersen, M.D.,6 and Marc S. Sabatine, M.D., M.P.H.2

for the FOURIER Steering Committee & Investigators1Ciccarone Center for the Prevention of Cardiovascular Disease, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD; 2Thrombolysis in Myocardial Infarction (TIMI) Study Group, Division of Cardiovascular Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA; 3Amgen, Thousand Oaks, CA; 4International Centre for Circulatory Health, National Heart and Lung Institute, Imperial College London, London; 5Sydney Medical School, National Health and

Medical Research Council Clinical Trials Centre, University of Sydney, Sydney; 6Oslo University Hospital, Ullevål and Medical Faculty, University of Oslo, Oslo

Background – Evolocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), reduced low-density lipoprotein cholesterol(LDL-C) and cardiovascular events in the FOURIER trial. The gold standard for LDL-C determination is beta-quantification (BQ), however it is mainly a research techniqueand LDL-C is usually estimated in clinical practice.

Objective – To investigate accuracy of two different methods for estimating LDL-C (Friedewald and Martin/Hopkins [M/H]) compared to gold standard BQ in patients with low LDL-C in FOURIER.

Methods – FOURIER was a randomized trial of evolocumab versus placebo added to statin therapy in 27,564 patients with atherosclerotic cardiovascular disease. To quantify LDL-C, FOURIER used the gold standard of BQ when the Friedewald estimate was <40 mg/dL. Friedewald LDL-C was estimated using a fixed conversion factor as TC – HDL-C – TG/5 whereas the Martin/Hopkins method used patient-specific TG:VLDL-C ratios to calculate LDL-C as TC – HDL-C – TG/personalized factor. This personalized factor, ranging from 3.1 to 9.5, was determined by the patient’s non-HDL-C and TG values available from the standard lipid profile. We created scatterplots of the two LDL-C estimates vs BQ, then examined regression lines, correlations, and mg/dL differences.

Results – A total of 56,624 observations (98.8% in Evolocumab pts) were recorded with Friedewald LDL-C <40 mg/dL. In scatterplots of estimated vs BQ LDL-C, M/H LDL-C appeared less prone to underestimation and more evenly distributed around the regression line (figure left) than Friedewald (figure right). Spearman’s correlation coefficient with BQ LDL-C was higher for M/H vs Friedewald LDL-C (0.918, [95% CI 0.916-0.919] vs 0.867, [95% CI 0.865-0.869]) and M/H LDL-C deviated less from observed values (Root MSE 4.32 [95% CI 4.25-4.39] vs 5.41 [95% CI 5.34-5.48] mg/dL). The median difference for M/H minus BQ LDL-C was -2 (25th to 75th: -4 to +1) mg/dL and for Friedewald minus BQ LDL-C was -4 (-8 to -1) mg/dL (p<0.001); differences were more pronounced in those with TGs ≥150 mg/dL: +2 (-1 to +6) vs -10 (-14 to -7) mg/dL (p<0.001). Overall, 77.1% of M/H LDL-C values were within 5 mg/dL and 97.4% within 10 mg/dL of BQ, which were significantly greater than respective proportions with Friedewald estimation (59.9% and 86.7%) (p<0.001).

Conclusion – In patients achieving low LDL-C with PCSK9 inhibition, the M/H method for LDL-C estimation correlates more closely than Friedewald LDL-C with gold standard BQ. These data suggest M/H estimation should be the preferred method to estimate LDL-C levels in such intensively treated patients.

Abstract

Introduction

Conclusions

Methods

Results

References

• Evolocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), reduced low-density lipoprotein cholesterol (LDL-C) and cardiovascular events in the FOURIER trial

• The gold standard for LDL-C determination is beta-quantification (BQ), also known as preparative ultracentrifugation, however it is mainly a research technique and LDL-C is usually estimated in clinical practice

• Recent studies have shown that Friedewald underestimates LDL-C at lower levels, which could result in undertreatment of high-risk patients

• A novel method (Martin/Hopkins [M/H]) appears to provide more accurate LDL-C, but has not been tested in PCSK9 inhibitor treated patients

• We aimed to investigate accuracy of M/H and Friedewald estimation compared to gold standard BQ in patients with low LDL-C in FOURIER






Abstract

Introduction

Conclusions

Methods

Results

References



• FOURIER was a randomized trial of evolocumab versus placebo added to statin therapy in 27,564 patients with atherosclerotic cardiovascular disease

• To quantify LDL-C, FOURIER used the gold standard of BQ when the Friedewald estimate was <40 mg/dL

• Friedewald LDL-C = TC – HDL-C – TG/5

• Martin/Hopkins LDL-C = TC – HDL-C – TG/patient-specific factor• This patient-specific factor, ranging from 3.1 to 9.5, was determined by the patient’s

non-HDL-C and TG values available from the standard lipid profile

• We created scatterplots of the two LDL-C estimates vs BQ, then examined regression lines, correlations, and mg/dL differences




Scatterplots of

estimated LDL-C

(X axis) vs BQ

LDL-C (Y axis)

Abstract

Introduction

Conclusions

Methods

Results

References






• 56,624 observations among 12,742 FOURIER patients with Friedewald LDL-C <40 mg/dL (98.8% recorded in Evolocumab pts): mean age 62.7±9.0 years, 22.6% women, 40.7% with triglycerides ≥150 mg/dL

• Median difference for M/H minus BQ LDL-C was -2 (25th to 75th: -4 to +1) mg/dL and for Friedewald minus BQ LDL-C was -4 (-8 to -1) mg/dL (p<0.001)

• Differences more pronounced if TGs ≥150 mg/dL: +2 (-1 to +6) vs -10 (-14 to -7) mg/dL (p<0.001)

• 22.9% of M/H LDL-C values were beyond +/-5 mg/dL and 2.6% beyond +/-10 mg/dL of BQ, significantly less than respective proportions with Friedewald estimation (40.1% and 13.3%) (p<0.001 for each)

• Differences again more pronounced if TGs ≥150 mg/dL: 10% vs 50.2% beyond +/-10 mg/dL of BQ

• Spearman's correlation coefficient with BQ LDL-C was higher for M/H vs Friedewald LDL-C (0.918, [95% CI 0.916-0.919] vs 0.867, [95% CI 0.865-0.869]) and M/H LDL-C deviated less from observed values (Root MSE 4.32 [95% CI 4.25-4.39] vs 5.41 [95% CI 5.34-5.48] mg/dL)

Abstract

Introduction

Conclusions

Methods

Results

References

CONCLUSIONS

• In patients achieving low LDL-C with PCSK9 inhibition,

compared with Friedewald, the Martin/Hopkins method more

closely approximates gold standard measurement.

• These data suggest that Martin/Hopkins estimation should be

the preferred method to estimate LDL-C levels and may prevent

undertreatment due to underestimation.

References:

• 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.

• 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.

• 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.

• 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.

• 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).

• 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.

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

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

• Giugliano RP, Pedersen TR, Park JG, et al. 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.Click Headings Above to

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martin/hopkins estimation, friedewald and beta- quantification … fourier nla... · 2018-07-06 ·...

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