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Measured LDL--an unnecessary expense or a customer service?

This article briefly describes our experience arising from the New Zealand national cardiovascular disease (CVD) and diabetes screening programmes which evaluates a patient's risk factors and probability of a CVD event over 5 years (1). For high risk individuals identified by the programmes, intensive lifestyle changes are recommended, supplemented by drug interventions for blood pressure lowering, diabetes control and lipid modification with regular follow up assessments. The programmes have increased early morning attendances for fasting blood tests leading to increased waiting times, patient dissatisfaction and stressed phlebotomists. Government targets are to have a five year risk prediction for 95% of the eligible population within the next two years so these pressures will continue. Screening for diabetes now utilises HbAlc for which fasting is not required.

But fasting is still a requirement for lipids under New Zealand guidelines, though a non-fasting sample for total cholesterol (TC)/high density lipoprotein cholesterol (HDL) ratio is acceptable for CVD risk assessment (2). Internationally, the Emerging Risk Factors Collaboration confirmed that non-fasting lipid measurements are acceptable for CVD risk screening (3) and, based on this evidence, some of our local Practitioners have already adopted non-fasting lipids for CVD screening. These developments have helped reduce the early morning pressures. However, our data show that 35% of all community-generated biochemistry requests have a lipid profile requested and >40% of these lipid requests still require fasting. This likely reflects the monitoring of lipid modification (Statin therapy) by estimation of low density lipoprotein cholesterol (LDL).

In New Zealand LDL is estimated by calculation using the Friedewald formula (4). This formula allows calculation of the contribution of very low density lipoprotein cholesterol (VLDL) to serum TC (LDL = TC - HDL - triglyceride/2.22)) with triglyceride/2.22 as proxy for the estimation of VLDL. The current national guidelines state that a fasting sample is mandatory due to effect of food intake on the triglyceride which causes the equation to 'overestimate' VLDL and, therefore, artefactually 'underestimate' LDL. Internationally, measured LDL methods (LDLm) were introduced to overcome this shortcoming (5) and we decided to investigate whether this approach could further reduce the need for patient fasting.

We used the 2nd generation Roche LDL-C plus method running on a Cobas 6000 analyser. The method principle is a homogenous enzymatic cholesterol assay (cholesterol esterase, cholesterol oxidase/peroxidase coupling reaction) modified by the addition of a non-ionic detergent, a sugar compound and magnesium which enables the selective determination of LDL (6). The method is standardised against the reference beta quantification method and Roche data indicates little interference from high levels of VLDL, chylomicrons and triglyceride. We calculated LDL (LDLc) by the Friedewald equation using Roche TC, HDL and triglyceride reagents on the same analyser. Application parameters and calibrations were as per the manufacturer's recommendations. Samples were freshly drawn lithium-heparin plasma and fasting status determined by direct questioning of the patients.

Data on 543 samples (243 fasting, 300 non-fasting) is summarised in Figure 1. The difference between the two LDL methods (LDLc minus LDLm) is plotted against the triglyceride in the same sample. It can be seen that at lower triglyceride levels the LDLm has a negative bias compared to LDLc but at triglyceride levels >2.5mmol/L the LDLc has an increasing negative bias to LDLm. Plotting fasting and non-fasting data separately revealed exactly the same "tip over" point (2.5mmol/L).

Comparing all samples with triglyceride <2.5mmol/L showed a strong correlation between the two methods (Figure 2). Our data supports the conclusions of van Deventer et al, who compared LDLc and multiple LDLm assays with reference methods (6). They also found lower LDLm levels compared to LDLc in fasting samples but found LDLc more accurate compared to reference methods. With raised triglyceride, LDLc became negative compared to LDLm which was also closer to the reference method target. Their "tip over" point was a triglyceride of 2.3mmol/L.

We conclude that it is the triglyceride level that differentiates, not fasting status, and we conclude it is necessary to estimate LDLm only on patients whose triglyceride levels are >2.5mmol/L (fasting or non-fasting). This was achieved by programming an appropriate rule in our computer middleware (IT3000, Roche Diagnostics). If triglyceride [greater than or equal to] 2.5 mmol/L, LDLm is automatically added to the lipid profile, the LDLc result nullified and an appropriate interpretive comment added. This rule operates reflexively--the sample is re-sampled for a LDLm assay before the sample rack leaves the analyser. No operator input is required and auto-validation completes the reporting. By combining the two methods in this way we are able to give more consistency to our LDL results and target LDLm to where it is most effective. The reflex rule approach also minimises extra reagent costs which has been an impediment to the use of LDLm in NZ.

In Kaitaia our data indicate an LDLm added to 18% of lipid requests, though this may vary in other communities. Current reagent, calibration and QC costs approximates to an extra $1 per reportable sample. Obviously, for larger laboratories this could be a significant reagent cost increase, but this should be set against the appreciable benefits, for the laboratory and the wider local community. For doctors, it allows patients to be referred to the laboratory straight from the health centre thus improving result turn-around-time. For patients, it eliminates the need for overnight fasting which many find onerous, particularly if repeated for therapy monitoring. It gives flexibility of attendance and, there is no need for patients to return home from the GP surgery to fast overnight and return for a blood test --a problem for remote communities. For the laboratory, it removes uncertainty about sample validity and assures accurate LDL results regardless of patient fasting status or diagnosis. The net effect would be to reduce early morning phlebotomy queuing, reduce patient waiting times, increase customer satisfaction and encourage patient compliance with the screening programmes.

In Kaitaia, our patient attendance time profiles have changed in the last year with our peak now at 10.30-11.00am with more patients attending after 2pm. Complete elimination of the need for fasting would continue this process but given the demonstrated bias between LDLm and LDLc an amendment to the national guidelines regarding the exact role of LDLm may be required to achieve this aim.

The current practice of laboratories reporting inaccurate LDLc results in samples with raised triglyceride should also be reviewed. In summary, LDLm is an opportunity for New Zealand laboratories to manage their phlebotomy services better and also contribute cost effectively to the well being of their local population by encouraging compliance with the national CVD screening programme. Targeted LDLm should be considered for wider application in New Zealand.

Acknowledgements

I am grateful to Vivien Goldsmith, Laboratory Manager, Northland District Health Board for her professional support and encouragement as this local initiative developed.

Author information

Alan Simkins, MNZIMLS, Charge Laboratory Scientist

Laboratory, Kaitaia Hospital, Redan Road, Kaitaia, Northland

Email: alan.simkins@northlanddhb.org.nz

References

(1.) Bannink L, Wells S, Broad J, Riddell T, Jackson R. Web-based assessment of cardiovascular disease risk in primary care practice in New Zealand: the first 18,000 patients (PREDICT CVD-1). N Z Med J 2006; 119(1245): U2313.

(2.) New Zealand Guidelines Group. New Zealand Primary Care Handbook (3rd ed.) New Zealand Guidelines Group, Wellington, 2012. http://www. health.govt. nz/publication/new-zealand-primary-care-handbook-2012.

(3.) Emerging Risk Factors Collaboration, Di Angelantonio E, Sarwar N, Perry P, Kaptoge S, Ray KK, et al. Major lipids, apolipoproteins and risk of vascular disease. JAMA 2009; 302: 1993-2000.

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

(5.) Nauck M, Warnick GR, Rifai N. Methods for measurement of LDL-cholesterol: a critical assessment of direct measurement by homogenous assays versus calculation. Clin Chem 2002; 48: 236-254.

(6.) van Deventer HE, Miller WG, Myers GL, Sakurabayashi I, Bachmann LM, Caudill SP, et al. Non-HDL assays show improved accuracy for cardiovascular risk score classification compared to direct or calculated LDL cholesterol in a dyslipaemic population. Clin Chem 2011; 57: 490-501
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Author:Simkins, Alan
Publication:New Zealand Journal of Medical Laboratory Science
Date:Apr 1, 2013
Words:1354
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