NIHR Signal Annual lipid monitoring places more individuals in treatment and saves money long-term compared with less frequent monitoring

Published on 23 February 2016

Annual testing to monitor blood lipids (fat and cholesterol) was both effective and saved money long term in by reducing cardiovascular disease in people with or without known heart disease.

Given the relatively low cost of treating high lipids (typically by using statins) it was more cost effective to over-treat people than to under-treat them.

The findings of this detailed modelling study are broadly in line with guidance. They also add clarity to previous uncertainties around the frequency of lipid monitoring and its relationship to diagnosis, prognosis and treatment.

More information is needed on patient willingness to be treated when they might not be experiencing any symptoms and on the long-term safety profile of some statins.

Annual lipid monitoring places more individuals in treatment and saves money long-term compared with less frequent monitoring

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Why was this study needed?

Cardiovascular disease causes almost a third of deaths in the UK, many of which are potentially preventable. Measuring blood lipids helps identify those at risk and guides treatment with statins to lower blood lipids. Along with measuring blood pressure and assessing other risk factors such as smoking, it is used routinely in the UK to assess a person’s risk of future heart attack or stroke. An Oxfordshire based study showed that lipid testing had increased more than 15-fold in the last 20 years in this region and UK expenditure on statin treatment was more than £800 million in 2011. Despite the popularity of lipid testing there is uncertainty about how often it should be tested and which lipid measure or combination of measures is best.

This study aimed to estimate the clinical and economic value of using different lipid measurements and different lipid testing intervals for preventing cardiovascular disease. In particular, it explored the impact of natural biological lipid level variation and measurement error – so called “noise” – on the value of different lipid-monitoring strategies.

What did this study do?

This modelling study incorporated data from two systematic reviews and patient level data from the UK and Japan to reach its predictions.

A systematic review of prospective studies investigated the ability of different lipid markers (and their ratios) to predict cardiovascular events (e.g. non-fatal heart attacks and strokes), deaths from cardiovascular disease and death from any cause.

A second systematic review pooled the results from trials to estimate the lipid lowering effects of a high-intensity statin – atorvastatin – at different doses.

A third data source, individual health records from people attending a GP in the UK and from a Japanese study, was used to study variability in lipids over time, including both natural biological variation and variation due to measurement imprecision (noise).

The final step was to estimate the likely cost of different lipid monitoring strategies, taking into account lipid variability, test accuracy (false positives and negatives) and quality of life.

What did it find?

  • A range of lipid blood measures (see Definitions) showed similar ability to predict risk of cardiovascular events. In people not already taking statins, the most predictive measures were non-HDL cholesterol, ApoB and composite measures (ratios of LDL/HDL cholesterol and TC/HDL). Other associations were smaller.
  • For all the different lipid tests, “noise” or biological variation and measurement error make up 25% of the variation in measurements on people who are not already taking statins or using lifestyle measures to reduce their lipid levels. This means that many observed changes in repeat rest results are not “true” differences.
  • Overall, to prevent cardiovascular disease and be cost effective, annual lipid monitoring was more beneficial compared with less frequent approaches. This applied to primary prevention in people with 10%, 15% or 20% risk of cardiovascular disease over ten years according to the Qrisk score and those already with heart disease (secondary prevention).
  • When measuring lipids more frequently, for example, annually instead of every five years, there is a trade-off between detecting more people who are at risk and incorrectly classifying (and treating) others who are not at risk.

What does current guidance say on this issue?

A 2014 NICE guideline recommends ongoing assessment of cardiovascular disease risk for people over 40 years old using risk scores. Targeted comprehensive assessment should only be carried out for those shown to have more than 10% risk of cardiovascular disease over ten years. It recommends against comprehensive assessment for everyone over 40 years old.

Before starting medication, such as statins, to reduce blood lipid levels the guideline recommends taking an initial blood test to include measuring total cholesterol, HDL cholesterol, non‑HDL cholesterol and triglyceride concentrations. Statins chosen for treatment should be high intensity statins, such as atorvastatin (see Definitions). For people already taking statins to reduce their blood lipids, the NICE guideline recommends annual review, which may be informed by fasting lipid measurements.

What are the implications?

This modelling study’s findings are broadly in line with guidance. The findings clarify issues on blood test monitoring and its relationship to diagnosis, prognosis and treatment that are more complex than they may first seem.

Whichever test is used, it can be difficult to determine a person’s cardiovascular disease risk exactly, as variation in their repeat test results may simply be due to “noise”. However, statin treatment and monitoring are relatively cheap, whereas the consequences of cardiovascular disease are severe and costly to individuals, society and health services. So it is more cost effective to over-treat than under-treat.

Further research is needed into whether patients are prepared to take statins in the long term, with potential side effects, to protect against future ill-health.

Citation and Funding

Perera R, McFadden E, McLellan J, et al. Optimal strategies for monitoring lipid levels in patients at risk or with cardiovascular disease: a systematic review with statistical and cost-effectiveness modelling. Health Technol Assess 2015;(19):1-402.

This project was funded by the National Institute for Health Research Health Technology Assessment programme (project number 10/97/01).

Bibliography

Heart UK. Cholesterol – know your numbers. Maidenhead: Heart UK; 2015.

NICE. Cardiovascular disease: risk assessment and reduction, including lipid modification. CG181. London: National Institute for Health and Care Excellence; 2014.

Why was this study needed?

Cardiovascular disease causes almost a third of deaths in the UK, many of which are potentially preventable. Measuring blood lipids helps identify those at risk and guides treatment with statins to lower blood lipids. Along with measuring blood pressure and assessing other risk factors such as smoking, it is used routinely in the UK to assess a person’s risk of future heart attack or stroke. An Oxfordshire based study showed that lipid testing had increased more than 15-fold in the last 20 years in this region and UK expenditure on statin treatment was more than £800 million in 2011. Despite the popularity of lipid testing there is uncertainty about how often it should be tested and which lipid measure or combination of measures is best.

This study aimed to estimate the clinical and economic value of using different lipid measurements and different lipid testing intervals for preventing cardiovascular disease. In particular, it explored the impact of natural biological lipid level variation and measurement error – so called “noise” – on the value of different lipid-monitoring strategies.

What did this study do?

This modelling study incorporated data from two systematic reviews and patient level data from the UK and Japan to reach its predictions.

A systematic review of prospective studies investigated the ability of different lipid markers (and their ratios) to predict cardiovascular events (e.g. non-fatal heart attacks and strokes), deaths from cardiovascular disease and death from any cause.

A second systematic review pooled the results from trials to estimate the lipid lowering effects of a high-intensity statin – atorvastatin – at different doses.

A third data source, individual health records from people attending a GP in the UK and from a Japanese study, was used to study variability in lipids over time, including both natural biological variation and variation due to measurement imprecision (noise).

The final step was to estimate the likely cost of different lipid monitoring strategies, taking into account lipid variability, test accuracy (false positives and negatives) and quality of life.

What did it find?

  • A range of lipid blood measures (see Definitions) showed similar ability to predict risk of cardiovascular events. In people not already taking statins, the most predictive measures were non-HDL cholesterol, ApoB and composite measures (ratios of LDL/HDL cholesterol and TC/HDL). Other associations were smaller.
  • For all the different lipid tests, “noise” or biological variation and measurement error make up 25% of the variation in measurements on people who are not already taking statins or using lifestyle measures to reduce their lipid levels. This means that many observed changes in repeat rest results are not “true” differences.
  • Overall, to prevent cardiovascular disease and be cost effective, annual lipid monitoring was more beneficial compared with less frequent approaches. This applied to primary prevention in people with 10%, 15% or 20% risk of cardiovascular disease over ten years according to the Qrisk score and those already with heart disease (secondary prevention).
  • When measuring lipids more frequently, for example, annually instead of every five years, there is a trade-off between detecting more people who are at risk and incorrectly classifying (and treating) others who are not at risk.

What does current guidance say on this issue?

A 2014 NICE guideline recommends ongoing assessment of cardiovascular disease risk for people over 40 years old using risk scores. Targeted comprehensive assessment should only be carried out for those shown to have more than 10% risk of cardiovascular disease over ten years. It recommends against comprehensive assessment for everyone over 40 years old.

Before starting medication, such as statins, to reduce blood lipid levels the guideline recommends taking an initial blood test to include measuring total cholesterol, HDL cholesterol, non‑HDL cholesterol and triglyceride concentrations. Statins chosen for treatment should be high intensity statins, such as atorvastatin (see Definitions). For people already taking statins to reduce their blood lipids, the NICE guideline recommends annual review, which may be informed by fasting lipid measurements.

What are the implications?

This modelling study’s findings are broadly in line with guidance. The findings clarify issues on blood test monitoring and its relationship to diagnosis, prognosis and treatment that are more complex than they may first seem.

Whichever test is used, it can be difficult to determine a person’s cardiovascular disease risk exactly, as variation in their repeat test results may simply be due to “noise”. However, statin treatment and monitoring are relatively cheap, whereas the consequences of cardiovascular disease are severe and costly to individuals, society and health services. So it is more cost effective to over-treat than under-treat.

Further research is needed into whether patients are prepared to take statins in the long term, with potential side effects, to protect against future ill-health.

Citation and Funding

Perera R, McFadden E, McLellan J, et al. Optimal strategies for monitoring lipid levels in patients at risk or with cardiovascular disease: a systematic review with statistical and cost-effectiveness modelling. Health Technol Assess 2015;(19):1-402.

This project was funded by the National Institute for Health Research Health Technology Assessment programme (project number 10/97/01).

Bibliography

Heart UK. Cholesterol – know your numbers. Maidenhead: Heart UK; 2015.

NICE. Cardiovascular disease: risk assessment and reduction, including lipid modification. CG181. London: National Institute for Health and Care Excellence; 2014.

Optimal strategies for monitoring lipid levels in patients at risk or with cardiovascular disease: a systematic review with statistical and cost-effectiveness modelling

Published on 19 December 2015

Perera, R.,McFadden, E.,McLellan, J.,Lung, T.,Clarke, P.,Perez, T.,Fanshawe, T.,Dalton, A.,Farmer, A.,Glasziou, P.,Takahashi, O.,Stevens, J.,Irwig, L.,Hirst, J.,Stevens, S.,Leslie, A.,Ohde, S.,Deshpande, G.,Urayama, K.,Shine, B.,Stevens, R.

Health Technol Assess Volume 19 , 2015

BACKGROUND: Various lipid measurements in monitoring/screening programmes can be used, alone or in cardiovascular risk scores, to guide treatment for prevention of cardiovascular disease (CVD). Because some changes in lipids are due to variability rather than true change, the value of lipid-monitoring strategies needs evaluation. OBJECTIVE: To determine clinical value and cost-effectiveness of different monitoring intervals and different lipid measures for primary and secondary prevention of CVD. DATA SOURCES: We searched databases and clinical trials registers from 2007 (including the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, the Clinical Trials Register, the Current Controlled Trials register, and the Cumulative Index to Nursing and Allied Health Literature) to update and extend previous systematic reviews. Patient-level data from the Clinical Practice Research Datalink and St Luke's Hospital, Japan, were used in statistical modelling. Utilities and health-care costs were drawn from the literature. METHODS: In two meta-analyses, we used prospective studies to examine associations of lipids with CVD and mortality, and randomised controlled trials to estimate lipid-lowering effects of atorvastatin doses. Patient-level data were used to estimate progression and variability of lipid measurements over time, and hence to model lipid-monitoring strategies. Results are expressed as rates of true-/false-positive and true-/false-negative tests for high lipid or high CVD risk. We estimated incremental costs per quality-adjusted life-year. RESULTS: A total of 115 publications reported strength of association between different lipid measures and CVD events in 138 data sets. The summary adjusted hazard ratio per standard deviation of total cholesterol (TC) to high-density lipoprotein (HDL) cholesterol ratio was 1.25 (95% confidence interval 1.15 to 1.35) for CVD in a primary prevention population but heterogeneity was high (I (2) = 98%); similar results were observed for non-HDL cholesterol, apolipoprotein B and other ratio measures. Associations were smaller for other single lipid measures. Across 10 trials, low-dose atorvastatin (10 and 20 mg) effects ranged from a TC reduction of 0.92 mmol/l to 2.07 mmol/l, and low-density lipoprotein reduction of between 0.88 mmol/l and 1.86 mmol/l. Effects of 40 mg and 80 mg were reported by one trial each. For primary prevention, over a 3-year period, we estimate annual monitoring would unnecessarily treat 9 per 1000 more men (28 vs. 19 per 1000) and 5 per 1000 more women (17 vs. 12 per 1000) than monitoring every 3 years. However, annual monitoring would also undertreat 9 per 1000 fewer men (7 vs. 16 per 1000) and 4 per 1000 fewer women (7 vs. 11 per 1000) than monitoring at 3-year intervals. For secondary prevention, over a 3-year period, annual monitoring would increase unnecessary treatment changes by 66 per 1000 men and 31 per 1000 women, and decrease undertreatment by 29 per 1000 men and 28 per 1000 men, compared with monitoring every 3 years. In cost-effectiveness, strategies with increased screening/monitoring dominate. Exploratory analyses found that any unknown harms of statins would need utility decrements as large as 0.08 (men) to 0.11 (women) per statin user to reverse this finding in primary prevention. LIMITATION: Heterogeneity in meta-analyses. CONCLUSIONS: While acknowledging known and potential unknown harms of statins, we find that more frequent monitoring strategies are cost-effective compared with others. Regular lipid monitoring in those with and without CVD is likely to be beneficial to patients and to the health service. Future research should include trials of the benefits and harms of atorvastatin 40 and 80 mg, large-scale surveillance of statin safety, and investigation of the effect of monitoring on medication adherence. STUDY REGISTRATION: This study is registered as PROSPERO CRD42013003727. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

The NHS Choices website explains that cholesterol is a fatty substance known as a lipid and is vital for the normal functioning of the body. It's mainly made by the liver, but can also be found in some foods.

Cholesterol is carried in the blood by proteins, and when the two combine they're called lipoproteins. The two main types of lipoprotein are:

  • High-density lipoprotein (HDL) – which carries cholesterol away from the cells and back to the liver, where it's either broken down or passed out of the body as a waste product. For this reason, HDL is referred to as "good cholesterol" and higher levels are better.
  • Low-density lipoprotein (LDL) – which carries cholesterol to the cells that need it. If there's too much cholesterol for the cells to use, it can build up in the artery walls, leading to disease of the arteries. For this reason, LDL is known as "bad cholesterol".

The blood lipid test is used to determine the amount of bad cholesterol (low-density lipoprotein, or LDL), good cholesterol (high-density lipoprotein, or HDL) and triglycerides (other fatty substances) in your blood, for initial diagnosis and monitoring of lipid levels and cardiovascular risk. The recommended cholesterol levels in the blood vary between those with a higher or lower risk of developing arterial disease. Other measures include Total Cholesterol (TC) and the TC: HDL ratio.

Expert commentary

This review shows that there is not much difference between different lipid measures in terms of predicting future cardiovascular events and mortality or all-cause mortality. Therefore, we can use measures that are easiest to do, most widely available and cost the least.

Approximately one quarter of changes in lipid levels can be attributed to measurement error (noise), which suggests that short-term changes should not lead to treatment decisions. Time we take out the noise and look for a more precise test?

Paradoxically, treating patients based on this noise was found to avoid cardiovascular events and mortality because overtreatment is better than under treatment. Therefore shorter monitoring intervals (one/two years) result in better outcomes at lower costs than longer monitoring intervals.

Dr Ann Van den Bruel, Associate Professor, Director NIHR Diagnostic Evidence Cooperative Oxford, University of Oxford

Author commentary

This study brings together evidence on the relationship between different lipid markers and cardiovascular disease and the extent to which measurement error and biological variability, rather than true change in measures, influence treatment decisions. It uses cost-effectiveness modelling to compare different monitoring strategies. Annual monitoring is likely to be effective and cost-saving compared to less frequent testing. As novel tests and treatments for cardiovascular risk become available, this study provides a framework in which to integrate new tests and treatments, and will generate evidence to support future policy.

Professor Andrew Farmer, Professor of General Practice, University of Oxford