Dr Martin Duerden summarises the main changes to NICE’s updated guidance on lipid modification and explores the challenges to primary care that will result

  • Cardiovascular disease remains a major cause of morbidity and is responsible for a third of all deaths in the UK
  • The new clinical guideline for lipid modification (NICE CG181) increases the number of people eligible for statin treatment in England by 4.5 million
  • The change in threshold for offering primary prevention to those with a greater than 10% 10-year risk of cardiovascular events is justified by clear evidence of benefit, very small risk of harm, and the recent considerable reduction in the cost of statins
  • Atorvastatin 20 mg daily, a ‘high intensity’ dose, should be offered as the initial intervention for primary prevention as it will achieve a 40% reduction in non-HDL cholesterol in most people; this reduction conveys greatest benefit
  • Patients should be offered an annual medication review, and measuring non-fasting lipid levels may help in informing and supporting this process
  • Non-HDL cholesterol can be measured without the need for fasting lipids and provides a good indicator of treatment effect:
    • laboratories will need to change their reports and clinicians will need to get used to the new values 
  • Atorvastatin 80 mg daily should be used in all people with established CVD: 
    • a lower dose or alternative statin should be used if this dose is not tolerated
  • Perhaps the biggest challenge will be the need, in offering statins to people for primary prevention, to explore their beliefs and values, communicate risk and benefit, and help them reach a decision on intervention.
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CG=clinical guideline

In 2014, NICE issued Clinical Guideline (CG) 181 on Lipid modification—cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease (available at: www.nice.org.uk/guidance/cg181).1 NICE CG181 is an update of the 2008 NICE guideline on lipid modification (CG67) and Technology Appraisal (TA) 94 on statins, and also updates and incorporates other guidance on lipid treatment from NICE guidelines including: diabetes (CG15 and CG66/87,)2,3 and chronic kidney disease (CG73, now CG182).4,5 It is fair to say that the lipid modification and cardiovascular risk assessment recommendations have been controversial: various commentators have criticised the guideline over the lower thresholds and large increase in the number of people now eligible for statins, and raised the spectre of over-medicalisation6 and ‘mass statinisation’.7 Perhaps surprisingly, some of the press coverage has been positive and recognises the scale of benefit that could be achieved if the guidelines are implemented.8

 
Despite the controversy, the Guideline Development Group (GDG) was of the opinion that these changes in CG181 were justified, as the evidence that people can benefit from treatment is now much clearer than it was in 2008; alongside this, the cost of the drugs has reduced dramatically with the advent of cheaper generics. It is also now more evident, despite anecdotes to the contrary, that statin drugs are remarkably free of adverse effects.9,10 The issue about whether people without overt cardiovascular disease (CVD) (i.e. those eligible for primary prevention) wish to receive these interventions has become a matter of individual choice. It is interesting that the level of absolute benefit is of a similar order of magnitude to that seen with treatments for mild-to-moderate hypertension;5 it may be that a cultural shift to greater acceptance of statin treatment as an option to augment lifestyle changes is now required.

Cardiovascular disease is a major threat to health

One reason for wishing to prevent or delay CVD and death in a large proportion of the population is that over one half of us will have a heart attack or stroke in our lifetime and a third of us will die from this. Cardiovascular disease is the leading cause of death in England and Wales and in 2010, 180,000 people died from CVD;1 around 80,000 of these deaths were caused by coronary heart disease and 49,000 by strokes, and 70% of the deaths were in men. Cardiovascular disease death rates peaked in the 1970s and 1980s, but have more than halved since that time; it is interesting to note that rates have fallen more rapidly in older age groups compared with younger ones, with an approximately 50% reduction in the 55–64 year age group compared with a 20% reduction in men aged 35–44 years.1 Cardiovascular disease is also more common where there is social deprivation and also in people in the UK of South Asian origin.11 As obesity levels rise and associated type 2 diabetes becomes more prevalent, there is a clear need to maximise preventative interventions in as many people as possible who are at risk.

Benefits and scale of treatment

NICE has estimated that if the recommendations in CG181 on primary prevention are implemented (i.e. offering treatment to people with a greater than 10% 10-year cardiovascular risk), up to 8000 lives could be saved every 3 years. The impact on CVD events is also significant and this change could prevent up to 28,000 heart attacks and 16,000 strokes each year. To achieve this, it is estimated that in England, 4.5 million extra people will now be offered a statin.5 At the previous 20% level of risk recommended in the NICE 2008 guideline, 13 million people were eligible for treatment, but only around 7 million of these individuals are currently receiving prescriptions.6 It is estimated that these increases in prescribing as a result of updated recommendations in NICE CG181 will raise overall drug costs by more than £52 million a year (the overall drug budget is over £10 billion). To put this figure into context, in 2005 atorvastatin cost the NHS in England £400 million. In 2013, this figure was less than £50 million because of the much cheaper cost of generic atorvastatin. For simvastatin, the cost was £100 million in 2005 and just over £50 million in 2013.12

Priorities for implementation

See Box 1 below for the recommendations identified in NICE CG181 as key priorities for implementation.1


Box 1: NICE Clinical Guideline 181—key priorities for implementation1

Identifying and assessing cardiovascular disease risk

  • For the primary prevention of CVD in primary care, use a systematic strategy to identify people who are likely to be at high risk 
  • Prioritise people for a full formal risk assessment if their estimated 10-year risk of CVD is 10% or more 
  • Use the QRISK2®13 risk assessment tool to assess CVD risk for the primary prevention of CVD in people up to and including age 84 years
  • Do not use a risk assessment tool to assess CVD risk in people with an eGFR less than 60 ml/min/1.73 m2 and/or albuminuria;a these people are at increased risk of CVD. (NB: See recommendation 1.3.27 for advice on treatment with statins for people with chronic kidney disease.)

Lipid modification therapy for the primary and secondary prevention of CVD

  • Before starting lipid modification therapy for the primary prevention of CVD, take at least one lipid sample to measure a full lipid profile. This should include measurement of total cholesterol, HDL cholesterol, non-HDL cholesterol, and triglyceride concentrations. A fasting sample is not needed 
  • Offer atorvastatin 20 mg for the primary prevention of CVD to people who have a 10% or greater 10-year risk of developing CVD.* Estimate the level of risk using the QRISK2 assessment tool
  • Start statin treatment in people with CVD with atorvastatin 80 mg.b Use a lower dose of atorvastatin if any of the following apply:
    • potential drug interactions 
    • high risk of adverse effects
    • patient preference 
  • Measure total cholesterol, HDL cholesterol, and non-HDL cholesterol in all people who have been started on high intensity statin treatment at 3 months of treatment and aim for a greater than 40% reduction in non-HDL cholesterol. If a greater than 40% reduction in non-HDL cholesterol is not achieved:
    • discuss adherence and timing of dose 
    • optimise adherence to diet and lifestyle measures
    • consider increasing dose if started on less than atorvastatin 80 mg and the person is judged to be at higher risk because of comorbidities, risk score, or using clinical judgement.

[This recommendation updates and replaces recommendation 1.10.2.7 from Type 1 diabetes (NICE CG15)].2

aPeople on renal replacement therapy are outside the scope of this guideline.

b At the time of publication of NICE CG181 (July 2014), atorvastatin did not have a UK marketing authorisation for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council’s Good practice in prescribing and managing medicines and devices14 for further information.

*includes those with type 2 diabetes

CVD=cardiovascular disease; eGFR=estimated glomerular filtration rate; HDL=high-density lipoprotein; CG=clinical guideline

Adapted from: NICE (2014). Lipid modification: cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease. Clinical Guideline 181. Available at: www.nice.org.uk/guidance/cg181  Reproduced with permission.


What are the big changes in clinical practice?

Risk assessment for primary prevention, including in people with type 2 diabetes, using QRISK2® 

NICE CG181 recommends a ‘systematic strategy to identify people who are likely to be at high risk’ followed by a ‘a full formal risk assessment if their estimated 10-year risk of CVD is 10% or more’.An important change is the recommendation to use QRISK2® (see www.qrisk.org)13 as the preferred risk assessment tool for primary prevention in people aged up to and including 84 years, including in those people with type 2 diabetes. Any risk assessment tool provides only an approximate value of CVD risk and interpretation of risk scores should always reflect informed clinical judgement. The previous guideline in 2008 had recommended Framingham-based risk scores and although QRISK® was available at that time, the tool had not been formally validated. The GDG for the new guideline (CG181) was persuaded that QRISK2® is now well validated and has more accurate predictive power than Framingham-based approaches. Most importantly, QRISK2® is now included in the specification for GP computer systems in the UK.

A similar decision was made for type 2 diabetes. Previously, the United Kingdom Prospective Diabetes Study (UKPDS) risk prediction engine had been recommended (in NICE CG66 in 2008). The GDG felt that a more pragmatic option was to change to recommend QRISK2® as it is readily available, has good predictive accuracy, and does not require a different approach from that used for people without diabetes.
 
An important aspect of the web-based QRISK2® is that it can be used as a patient decision aid. It gives a graphical representation of the absolute risks of cardiovascular disease and provides a rough indication of the effects of intervention.

Reducing the threshold to 10%

A big challenge in terms of increasing numbers of people on treatment is the move from the greater than 20% 10-year risk threshold of a CVD event to a 10% threshold. Using this threshold, it can be estimated that 1 in 4 men and over 1 in 5 women aged between 30 and 85 years may now be eligible to be offered treatment.15 These proportions will be greater in more socially deprived areas.11 Ideally, people should consider lifestyle adjustments as the key option: stopping smoking, increasing exercise, modifying diet, and moderating alcohol; and NICE CG181 includes specific recommendations about lifestyle adjustments for all people at risk of, or with CVD.1 It may be, however, that some people will want statin treatment as well, and it has to be said that some individuals may wish this instead of lifestyle changes. Also, if the risk does not decrease as a result of lifestyle intervention, statins can be considered an ‘add on’. This major change was felt to be justified by the very low cost of generic statins and clear evidence of benefit at low levels of risk. This was set alongside the evidence that statin drugs have very few adverse effects.9,10

One criticism of the guideline has been the lack of information on absolute risks. This is partly because these values are different for different tiers of risk in individuals. For example, the number needed to treat (NNT) to prevent a major vascular event or death over 5 years has been estimated at 50 for those with a 15% 10-year risk, and 74 at a 10% level.16 It should be recognised, as previously mentioned above, that these values are similar to those for treating mild-to-moderate hypertension.
 

Initially offering atorvastatin 20 mg daily for primary prevention

For the purpose of NICE CG181, statins are grouped into three different intensity categories, according to the percentage reduction in cholesterol they produce (see Table 1, below).1
Table 1: Grouping of statins used in NICE CG181—Lipid Modification1*
Reduction in low-density lipoprotein cholesterol
Dose (mg/day) 5 10 20 40 80
fluvastatin - - 21%1 27%1 33%2
pravastatin - 20%1 24%1 29%1 -
simvastatin - 27%1 32%2 37%2 [42%]3,4
atorvastatin - 37%2 43%3 49%3 55%3
rosuvastatin 38%2 43%3 48%3 53%3 -
1 20%–30%: low intensity.
2 31%–40%: medium intensity.
3 Above 40%: high intensity.
4 Advice from the MHRA: there is an increased risk of myopathy associated with high-dose (80 mg) simvastatin. The 80 mg dose should be considered only in patients with severe hypercholesterolaemia and high risk of cardiovascular complications who have not achieved their treatment goals on lower doses, when the benefits are expected to outweigh the potential risks. 
*The information used to make the table is from Law M, Wald N, Rudnicka A. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta analysis. BMJ 2003; 326: 1423.
NICE (2014). Lipid modification: cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease. Clinical Guideline 181. Available at: www.nice.org.uk/guidance/cg181  Reproduced with permission.
The reduction in cardiovascular events was greatest for high-intensity treatment, when a more than 40% reduction in non-HDL cholesterol was achieved (NB: this is equivalent to a 40% reduction in LDL-cholesterol). The recommendation of ‘high intensity’ atorvastatin 20 mg daily as the initiation dose for primary prevention is made because this dose is cost effective, extremely well tolerated, relatively safe, and likely to achieve a 40% reduction in non-HDL cholesterol for many people.
 
There is also a move away from the simple ‘fire and forget’ strategy in primary prevention seen in CG67 in 2008, where a single dose was recommended and no monitoring was thought necessary. NICE CG181 advises an annual medication review and consideration of monitoring with an annual non-fasting cholesterol test. This can inform the discussion and support related lifestyle advice.

When to consider increasing atorvastatin dose up to 80 mg daily

A greater effect is seen with 80 mg atorvastatin, even in primary prevention, and increasing the dose should be considered if the 40% reduction in non-HDL cholesterol is not achieved. It seems sensible that greater emphasis should be given to increasing the dose up to 80 mg atorvastatin daily when the person is judged to be at the higher end of the risk spectrum because of comorbidities such as diabetes, risk score, or clinical judgement. Key to this is the terminology used by NICE for this recommendation. ‘Consider’ is used within NICE guidelines when there is confidence that an intervention will do more good than harm for most patients. In these circumstances, NICE advises that the choice of intervention, and whether or not to have the intervention at all, is more likely to depend on the patient’s values and preferences than in circumstances where there are stronger recommendations.

Give atorvastatin 80 mg daily to all people with a history of CVD

To give greatest benefit, the guideline recommends atorvastatin 80 mg daily for people who present with CVD (e.g. angina, myocardial infarction, transient ischaemic attack, stroke, or peripheral vascular disease). Many patients with recent myocardial infarction, or vascular events, are already receiving atorvastatin 80 mg in line with recommendations made in the 2008 guideline, particularly following restrictions in the use of high-dose simvastatin. If this proves problematic, a dose reduction or change of statin is suggested (see Table 1, above). There will be some people on a smaller dose, or taking simvastatin, and the option of changing or increasing should be discussed when patients next have a medication review. 

No need for fasting samples; use non-HDL cholesterol as a measure of treatment effect

The new guideline recommends the use of non-high density lipoprotein (non‑HDL) cholesterol rather than low-density lipoprotein (LDL) cholesterol. This allows a move away from measuring fasting lipids and also represents a change from using LDL-cholesterol as a crude measure of risk reduction. The reason for this is that LDL-cholesterol is usually estimated indirectly by a complicated formula involving triglycerides, HDL-cholesterol, and total cholesterol. Triglyceride estimation requires a fasting level to be consistent and reliable. There is now clear evidence that simply subtracting HDL-cholesterol from the total cholesterol level to give ‘non-HDL cholesterol’ measure provides a better estimate of treatment effect and of cardiovascular risk reduction.17 Using this approach will be generally easier, but requires a change in laboratory reporting. More importantly, clinicians will need to get used to the new range of figures derived by this method. 

No routine need for other lipid-modifying drugs

Unlike previous guidance, particularly that relating to diabetes, NICE CG181 advises against routinely offering fibrates, nicotinic acid (niacin), bile sequestrants (anion exchange resins), or omega-3 fatty acid compounds to prevent CVD. These may have a role in specialist management, for example in hypertriglyceridaemia. 

NICE CG181 recommends that people with primary (heterozygous-familial and non-familial) hypercholesterolaemia should be considered for ezetimibe treatment in line with NICE Technology Appraisal 32.1,18

The toughest challenge?

Perhaps the toughest challenge may be in identifying how practitioners individualise the recommendations of the guideline, intended for so many, for each person at the time of consultation, plus the added workload this might involve. Each person will have different beliefs and values and considerable skill is needed to explore these and reach a valid, shared approach to their management. This will require training and education for the healthcare professionals involved, in understanding what statins can do, what harms they may cause, and in communicating these risks. NICE is working on training materials that will help in this task. The pictorial information provided on the online QRISK2 calculator is an example of the kind of information that can be used to guide patient choice (see www.qrisk.org).
written by Dr David Jenner, NHS Alliance GMS contract/PBC Lead
  • NICE CG181 has major workload implications for primary care as it significantly increases the number of people recommended to take statins and also requires annual review of all these patients, with blood tests and a face-to-face consultation:
  • the added workload is likely to be far more of a barrier to implementation that the cost of the statins, which are now generic and of low cost
  • As yet, there is no recognition of the extra work for primary care in budget allocations, or any incentives in the QOF for 2015/2016
    • clinical commissioning groups will therefore need to discuss carefully with NHS England how the resources and incentives can be found to support primary care in implementing this guidance
  • Clinical commissioning groups should also discuss with local public health departments as to how NHS Health Checks and assessments of CVD risk can be targeted to those most at risk, as recommended in this guidance.
CG=clinical guideline

  1. NICE. Lipid modification: cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease. Clinical Guideline 181. NICE, 2014. Available at: www.nice.org.uk/guidance/cg181
  2. NICE. Type 1 diabetes: Diagnosis and management of type 1 diabetes in children, young people and adults. Clinical Guideline 15. NICE, 2014. Available at: www.nice.org.uk/guidance/cg15
  3. NICE. Type 2 diabetes: The management of type 2 diabetes. Clinical Guideline 87. NICE, 2009. Available at: www.nice.org.uk/guidance/cg87
  4. NICE. Chronic kidney disease: early identification and management of chronic kidney disease in adults in primary and secondary care. Clinical Guideline 182. NICE, 2014. Available at: www.nice.org.uk/guidance/cg182
  5. NICE website. News and features. Wider use of statins could cut deaths from heart disease. 18 July 2014. Available at: www.nice.org.uk/News/Article/wider-use-of-statins-could-cut-deaths-from-heart-disease (accessed 22 August 2014).
  6. BBC News. 18 July 2014. Statins: Millions more to get drugs in controversial plans. Available at: www.bbc.co.uk/news/health-28352290 (accessed 28 September 2014).
  7. Wise J. Open letter raises concerns about NICE guidance on statins. BMJ 2014; 348: g3937.
  8. The Independent. 18 July 2014. From: Prescribing statins more widely ‘could avert tragedy’, new medical guidelines suggest. Available at: www.independent.co.uk/news/science/prescribing-statins-more-widely-could-avert-tragedy-new-medical-guidelines-suggest-9613424.html (accessed 28 September 2014).
  9. Finegold J, Manisty C, Goldacre B et al. What proportion of symptomatic side effects in patients taking statins are genuinely caused by the drug? Systematic review of randomized placebo-controlled trials to aid individual patient choice. Eur J Preventive Cardiol 2014; 21 (4): 464–474.
  10. Macedo A, Taylor F, Casas J et al. Unintended effects of statins from observational studies in the general population: systematic review and meta-analysis. BMC Medicine 2014; 12: 51.
  11. Bhopal R. Epidemic of cardiovascular disease in South Asians. BMJ 2002; 324: 625–626.
  12. Health and Social Care Information Centre. Prescriptions dispensed in the community, statistics for England: 2003–2013. Available at: www.hscic.gov.uk/searchcatalogue?productid=14988&topics=0%2fPrescribing&sort=Most+recent&size=10&page=1#top (accessed 28 September 2014).
  13. University of Nottingham and EMIS. QRISK2-2014 risk calculator website. www.qrisk.org (accessed 26 August 2014).
  14. General Medical Council. Good practice in prescribing and managing medicines and devices. Prescribing guidance: Prescribing unlicensed medicines. London: GMC, 2013. Available at: www.gmc-uk.org/guidance/ethical_guidance/14327.asp (accessed 26 August 2014).
  15. NICE. CG181 Lipid modification: costing report. Available at: www.nice.org.uk/Guidance/CG181/Costing (accessed 27 September 2014).
  16. Ebrahim S, Taylor F, Brindle P. Statins for the primary prevention of cardiovascular disease. BMJ 2014; 348: g280.
  17. Di Angelantonio E, Sarwar N, Perry P et al. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 2009; 302 (18): 1993–2000.
  18. NICE. Ezetimibe for the treatment of primary (heterozygous-familial and non-familial)hypercholesterolaemia. NICE Technology Appraisal 132. NICE, 2007. Available at: www.nice.org.uk/guidance/TA132