Dr Alan Begg discusses how the NICE technology appraisal on ezetimibe will make it easier for GPs to reach QOF cholesterol targets

The recommendations from the recently published NICE technology appraisal (TA) on Ezetimibe for the treatment of primary hypercholesterolaemia1 (see Table 1) will make it easier for GPs to reach the cholesterol targets in the Quality and Outcomes Framework (QOF)2 (see Table 2).

The Secretary of State for Health in England has directed that the NHS should provide funding and resources for medicines and treatments recommended by this NICE TA, and in Wales patients and service users should be provided with effective treatment and care that conforms to NICE TA guidance. In Scotland, guidance issued by the Scottish Medicines Consortium (www.scottishmedicines.org.uk) usually reflects the recommendations in NICE TAs.

Table 1: NICE recommendations on the use of ezetimibe1

Ezetimibe should be:

  • Used in adults with:
      • primary heterozygous-familial hypercholesterolaemia
      • primary non-familial hypercholesterolaemia
  • Given as monotherapy if:
      • initial statin therapy is contraindicated
      • patient is intolerant to statin therapy
  • Co-administered with initial statin therapy if:
      • serum total or LDL cholesterol is not appropriately controlled after initial statin therapy titration or titration limited by intolerance
      • and consideration is being given to changing to an alternative statin
LDL=low-density lipoprotein

Table 2: QOF2 clinical indicators for cholesterol targets

No. Indicator
Points
Payment
stages
CHD 8 The percentage of patients with CHD whose last measured total cholesterol (measured in the previous 15 months) is ?5 mmol/l
17
40–70%
STROKE 8 The percentage of patients with stroke or TIA whose last measured total cholesterol (measured in the previous 15 months) is ?5 mmol/l
5
40–60%
DM 17 The percentage of patients with diabetes whose last measured total cholesterol within the previous 15 months is ?5 mmol/l
6
40–70%
 
Total points
28
 
CHD=coronary heart disease; TIA=transient ischaemic attack
 
 

Evidence for cholesterol lowering

Clinical trials have shown that lowering cholesterol reduces the risk of both a cardiovascular disease (CVD) event and mortality in those at increased risk. In a meta-analysis from 14 randomised statin trials, which included a total of 90,056 patients, the Cholesterol Treatment Trialists’ Collaboration showed that a 1 mmol/l reduction in low-density lipoprotein (LDL) cholesterol was associated with a 23% reduction in cases of non-fatal myocardial infarction or coronary heart disease death over a 5-year period. It also demonstrated a 21% reduction in major coronary events, revascularisation, and stroke.3 This outcome benefit has also been shown with non-statin cholesterol-lowering trials, and the pleiotropic effects of statins may not contribute to additional risk reduction other than that seen by cholesterol reduction.4–6

Mode of action

Ezetimibe acts by blocking the dietary and biliary absorption of cholesterol and plant sterols. It does not affect the uptake of triglycerides or fat-soluble vitamins, and, when combined with a statin, it provides complementary cholesterol reduction.1

The drug is well tolerated and the adverse effects of monotherapy, which are usually mild and transient, include:

  • headache
  • abdominal pain
  • diarrhoea.1

When given with a statin the common adverse effects are:

  • gastrointestinal upset
  • headache
  • fatigue
  • myalgia.1

However the long-term efficacy and safety of ezetimibe alone or in combination with a statin is unknown.

Effective cholesterol lowering

Ezetimibe is an effective cholesterol-lowering agent. When administered as monotherapy, its use leads to a statistically significant mean reduction in the total cholesterol level of 13.4% (95% confidence interval [CI] 14.2 to 12.6) when compared with placebo.1 On behalf of NICE, the assessment group carried out a meta-analysis of the randomised controlled trials on the use of ezetimibe to lower cholesterol in those whose cholesterol level was not controlled on a statin alone.6 Combined ezetimibe and statin therapy is associated with an additional mean reduction in total cholesterol of 10.4% (95% CI 11.1 to 9.6) from pre-statin treatment levels when compared with statin therapy alone.1

Extrapolation of the evidence

Although it was aware of the absence of any clinical benefit of lipid lowering with ezetimibe, the NICE Appraisal Committee was of the opinion that lowering LDL cholesterol, independent of the treatment used, was associated with improved CVD outcomes.6 On this basis it felt that treatment with ezetimibe to lower cholesterol will translate into a future reduction in cardiovascular events, even though, at present, the effect on cardiovascular morbidity and mortality is unknown.1

Cost-effectiveness

The NICE Appraisal Committee has concluded that, as a treatment option, the addition of ezetimibe to initial statin therapy is a cost-effective use of NHS resources when compared with switching to an alternative statin.1 It was aware that doubling the dose of statin therapy will only lead to a further 6% reduction of LDL cholesterol.1 From the different economic models assessed, there was one scenario that stood out as being the most cost effective. The incremental costs per quality adjusted life year gained of ezetimibe plus simvastatin compared with atorvastatin alone were all below £4600 regardless of age, sex, and CVD history. The estimated average annual drug costs of ezetimibe, ezetimibe plus simvastatin, and atorvastatin alone are listed in Table 3.

Table 3: Estimated average annual drug costsa

  Annual cost (£)
Ezetimibe 10 mg daily 342.97
Ezetimibe 10 mg + simvastatin 40 mg daily 360.05
Atorvastatin 40 mg daily 367.44
aNICE technology appraisal 132 costing statement:
www.nice.org.uk/guidance/index.jsp?action=download&o=38347National Institute for Health and Care Excellence (NICE) (2007) TA 132 Ezetimibe for the treatment of primary (heterozygous-familial and non-familial) hypercholesterolaemia. London: NICE. Available from www.nice.org.uk. Reproduced with permission

Reaching targets

The average total cholesterol concentration in adults in England is approximately 5.6 mmol/l, whereas in Scotland it is now 5.5 mmol/l.7 There is evidence to suggest that patients who have reached their QOF cholesterol target may be switched to a lower cost statin, such as simvastatin, without the need to resort to the use of an additional agent such as ezetimibe to maintain their target level. Usher-Smith et al. showed that there was no significant change to the mean total cholesterol of a group of patients switched from atorvastatin to simvastatin for cost-saving purposes.8 For others who have not reached their target cholesterol level, taking into consideration this NICE TA and the one on the use of statins for the prevention of cardiovascular events,9 a possible management approach for primary care is outlined in Figure 1.

Figure 1: Therapeutic lowering of cholesterol

Therapeutic lowering of cholesterol

CVD=cardiovascular disease

Resource impact

The guidance states there are 2% of patients with hypercholesterolaemia eligible for treatment who are unable to tolerate, or who have a contraindication to a statin, who may benefit from ezetimibe.10 The resource impact is not felt to be significant as the annual estimated drug cost of combination therapy is comparable with higher doses of more powerful lipid-lowering statins. These are currently used in those patients who fail to reach cholesterol target levels (Table 3).

Lower cholesterol targets

The current total cholesterol target in the QOF is ?5 mmol/l (see Table 2), although the Joint British Societies’ guidance recommends aiming for a lower target of <4 mmol/l.11 That guidance does, however, accept that there are no clinical trials that have looked at the benefits of lowering cholesterol to different levels in terms of less clinical events.

Dr Lester, the GP academic who heads the team that provides advice to the current negotiating teams for the QOF, has recently published her views on the future of quality measurement.12 The first of her suggestions for developing quality measurement in general practice is to expect higher achievement each year. A lower cholesterol target could be covered by this approach, although her preferred option is to rotate quality measures regularly, with the aim of providing improvements across an expanded range of disease categories not currently covered by QOF. This approach may take the pressure off GPs to achieve even lower cholesterol targets.

Click here for a related editorial on the ENHANCE trial results

  • NICE now recommends ezetimibe for use with a statin, or as monotherapy by those intolerant to statins to meet lipid-lowering targets
  • Ezetimibe increases the lipid-lowering effect of a statin by approximately 10%
  • There are, as yet, no definite clinical outcome data for ezetimibe
  • The combination of ezetimibe and simvastatin is currently cheaper than stronger statins but these latter drugs may become less expensive
  • One needs to look at the LDL cholesterol-lowering effect per purchasing pound when choosing lipid-lowering therapy
  • Ezetimibe 10 mg a month £26.31; simvastatin 40 mg a month £3.80a
  1. National Institute for Health and Care Excellence. Ezetimibe for the treatment of primary (heterozygous-familial and non-familial) hypercholesterolaemia. Technology Appraisal 132. London: NICE, 2007.
  2. Quality and outcomes framework guidance. www.bma.org.uk/ap.nsf/Content/qof06
  3. Baigent C, Keech A, Kearney P et al; Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005; 366 (9493): 1267–1278.
  4. Robinson J, Smith B, Maheshwari N, Schrott H. Pleiotropic effects of statins: benefit beyond cholesterol reduction? A meta-regression analysis. J Am Coll Cardiol 2005; 46 (10): 1855–1862.
  5. Gould A, Rossouw J, Santanello N et al. Cholesterol reduction yields clinical benefit: impact of statin trials. Circulation 1998; 97 (10): 946–952.
  6. Ezetimibe for the treatment of hypercholesterolaemia. www.nice.org.uk/nicemedia/pdf/Hyperchol_Ass_report.pdf
  7. The Scottish Health Survey 2003—Volume 1. www.scotland.gov.uk/Resource/Doc/76169/0019727.pdf
  8. Usher-Smith J, Ramsbottom T, Pearmain H, Kirby M. Evaluation of the cost savings and clinical outcomes of switching patients from atorvastatin to simvastatin and losartan to candesartan in a Primary Care setting. Int J Clin Pract 2007; 61 (1): 15–23.
  9. National Institute for Health and Care Excellence. Statins for the prevention of cardiovascular events. Technology Appraisal 94. London: NICE, 2006.
  10. www.nice.org.uk/guidance/index.jsp?action=download&o=38347
  11. JBS2: Joint British Societies’ Guidelines on Prevention of Cardiovascular Disease in Clinical Practice. Heart 2005; 91 (suppl v): v1–v52.
  12. Lester H, Roland M. Future of quality measurement. Br Med J 2007; 335 (7630): 1130–1131.G