Revised PBS criteria for lipid-modifying drugs (October 2006)

Published in NPS RADAR

Date published: About this date

Clinical content may change after this date. This information is not intended as a substitute for medical advice from a qualified health professional. Health professionals should rely on their own expertise and enquiries when providing medical advice or treatment.

How have the PBS criteria changed and why? | High-risk groups can be treated at any cholesterol concentration | Determining risk in people without symptomatic disease | Risk in specific patient populations | Lifestyle changes remain important | Use risk calculators as a guide to risk in primary prevention | Authority requirements for ezetimibe preparations have changed | Guidelines on lipid management | References

Summary

  • PBS lipid-modifying drug-eligibility criteria have changed to facilitate treatment according to risk of future cardiovascular events. The PBAC accepted that the benefits of lipid-modifying drugs increase proportionally with absolute risk, and that treating people at greatest risk will maximise health benefits and cost–effectiveness.
  • For people who are at highest absolute risk of a major cardiovascular event, statin or fibrate therapy is PBS subsidised regardless of cholesterol concentrations.
  • For people at lower cardiovascular risk, cholesterol thresholds remain part of the criteria for PBS-subsidised prescribing of statins and fibrates.
  • Diet and lifestyle measures are important in the management of cardiovascular risk, even when lipid-modifying therapy is used.
  • At the time of publication, ezetimibe preparations (Ezetrol and Vytorin) continue to be authority items.

How have the PBS criteria changed and why?

Changes to the Pharmaceutical Benefits Scheme (PBS) criteria for lipid-modifying drugs reflect current recommendations1 to treat according to overall cardiovascular risk rather than cholesterol concentrations alone. The PBS criteria aim to direct therapy to people at greatest risk of a major cardiovascular event. The changes assume that the benefits of lipid-modifying drugs increase proportionally with absolute risk, and that treating people at greatest risk will maximise health benefits and cost-effectiveness.

Evidence reviewed by the Pharmaceutical Benefits Advisory Committee (PBAC) included the Heart Protection Study (HPS)2, the United Kingdom Prospective Diabetes Study (UKPDS)3, Australian data on diabetes from the Australian National Diabetes Information Audit (ANDIAB) and the National Divisions Diabetes Program as well as input from experts.

Note: this NPS RADAR article was prepared using excerpts from the minutes of the PBAC meeting of July 2004 (personal communication, Secretary, PBAC).

High-risk groups can be treated at any cholesterol concentration

People with existing, symptomatic coronary heart disease (CHD), cerebrovascular disease or peripheral vascular disease have the highest 5-year absolute risk of a cardiovascular event — that risk was substantially reduced by treatment with simvastatin in the Heart Protection Study (n = 20 536).2,4 The benefits in this high risk population were similar regardless of pre-treatment cholesterol concentrations. The Heart Protection Study also included people considered high risk because of diabetes (90% of which was type 2 diabetes).

Statins are first line for treatment of hypercholesterolaemia and treatment can be initiated with any statin. Fibrates can be used for hypertriglyceridaemia, or in mixed dyslipidaemia when elevated triglyceride concentration is the predominant disorder. However, in people with existing vascular disease statins are recommended; they can be combined with fibrates if further triglyceride-lowering is required.1

The listing for CHD is specific to patients with symptomatic disease. Those with CHD diagnosed through investigations but who are asymptomatic are not known to have an equivalent level of absolute risk.

The PBAC review also sought to identify specific populations who were ‘CHD-risk equivalent’ — that is, those who had a similar level of risk to people with clinically manifest CHD, cerebrovascular disease or peripheral vascular disease. The CHD-risk-equivalent groups identified are shown in Table 1.

Table 1: PBS criteria for high-risk groups — eligible for PBS subsidy at any cholesterol concentration

Start drug treatment at any cholesterol concentration, concurrently with diet therapy
PATIENTS WITH SYMPTOMATIC DISEASE
Symptomatic disease Examples* Cardiovascular risk estimates (without treatment) considered by the PBAC
Coronary heart disease

or
Myocardial infarction, stable or unstable angina, coronary artery bypass graft, angioplasty 20–30% absolute risk of a major vascular event over 5 years2
Cerebrovascular disease

or
Stroke, transient cerebral ischaemia, carotid endarterectomy
Peripheral vascular disease Leg artery stenosis (including intermittent claudication), other occlusive disease or arterial surgery
OTHER HIGH-RISK POPULATIONS (coronary heart disease-risk equivalent)
High-risk diabetes mellitus
People with diabetes mellitus aged ≥ 60 years

or
People aged ≥ 60 years with diabetes of 10 years’ duration have a 20% to 30% risk of a first cardiovascular event over 10 years. Risk in people newly diagnosed at age 60 is about 17% over 10 years.
People with diabetes mellitus
with microalbuminuria (urinary albumin excretion rate of > 20 micrograms per minute or urinary albumin:creatinine ratio > 2.5 for males, > 3.5 for females)

or
Microalbuminuria confers 2–3 times higher risk than in diabetes without other risk factors
People with diabetes mellitus
who are Aboriginal or Torres Strait Islanders
Exact risk is unknown, but Aboriginal and Torres Strait Islander people have higher rates of cardiovascular disease and related mortality, diabetes develops earlier, and the population is younger; existing cardiovascular risk calculators cannot be used in this population
Family history of symptomatic coronary heart disease

In two or more first-degree relatives before age 55 years

or

In one or more first-degree relatives before age 45 years
Risk estimates for family history were not available

* Study populations included in Heart Protection study2

Major vascular event: Non-fatal myocardial infarction, death from coronary disease, stroke of any type, coronary or non-coronary revascularisation2

This estimate, used by the PBAC, is based on the UKPDS risk calculator which estimates risk in people with diabetes mellitus and no previous heart disease or stroke5

Determining risk in people without symptomatic disease

Some populations are known to have an elevated cardiovascular risk profile, but it is not clear whether there are benefits in lipid-modifying therapy when cholesterol concentrations are at or below target (unlike the high-risk populations discussed above). In these lower-risk populations, threshold cholesterol concentrations have been maintained in the PBS criteria (see Table 2).

Table 2: PBS criteria for lower risk groups — eligible for PBS subsidy according to cholesterol concentrations

Start drug therapy only when cholesterol remains above threshold after 6 weeks of diet therapy alone
Population Cholesterol thresholds required for PBS subsidy
Patients with diabetes (apart from high-risk groups — see Table 1) total-C > 5.5 mmol/L
Aboriginal and Torres Strait Islander people without diabetes or other high risk total-C > 6.5 mmol/L or
total-C > 5.5 mmol/L and HDL-C < 1 mmol/L
Patients with hypertension total-C > 6.5 mmol/L or
total-C > 5.5 mmol/L and HDL-C < 1 mmol/L
Patients with HDL cholesterol < 1 mmol/L total-C > 6.5 mmol/L
Familial hypercholesterolaemia identified by:
  • DNA mutation or
  • tendon xanthoma in the patient or first- or second-degree relative
≤ 18 years at treatment initiation
LDL-C > 4 mmol/L
> 18 years at treatment initiation
LDL-C > 5 mmol/L or total-C > 6.5 mmol/L or total-C > 5.5 mmol/L and HDL-C < 1 mmol/L
Family history of symptomatic CHD:
  • before age 60 years in one or more first-degree relatives
  • before age 50 years in one or more second-degree relatives
≤ 18 years at treatment initiation
LDL-C > 4 mmol/L
> 18 years at treatment initiation
LDL-C > 5 mmol/L or total-C > 6.5 mmol/L or total-C > 5.5 mmol/L and HDL-C < 1 mmol/L
High cholesterol in patients not eligible above who are:
  • men aged 35-75 years
  • postmenopausal women up to 75 years
total-C > 7.5 mmol/L or triglycerides > 4 mmol/L
Patients not otherwise included total-C > 9 mmol/L or triglycerides > 8 mmol/L

Risk in specific patient populations

The PBAC considered the evidence for maintaining cholesterol thresholds in the following specific populations.

People with diabetes

Diabetes mellitus increases the risk of a cardiovascular event, but the spectrum of risk depends on individual comorbidity and other factors such as age.1 Among people with diabetes, risk is greatest for those who also have symptomatic CHD, cerebrovascular or peripheral vascular disease, or who have microvascular complications.6,7 People aged over 60 years and from Aboriginal or Torres Strait Islander populations were considered to have similarly high risk.

People with diabetes who are not in the high-risk groups in Table 1 are eligible for PBS-subsidised lipid-modifying therapy when their total cholesterol concentration is > 5.5 mmol/L. Taking into account the overall risk profile of the Australian diabetes population, the PBAC estimated that the revised PBS criteria would allow treatment of 50% to 60% of all people with diabetes, compared with around 10% based on the previous criteria. (Note that treatment guidelines may recommend different cholesterol thresholds for people with diabetes, consult the relevant guidelines shown below).

Aboriginal and Torres Strait Islander people

Aboriginal and Torres Strait Islander people have higher rates of mortality from cardiovascular disease compared with the rest of the population.8 Proteinuria and microalbuminuria (with or without diabetes) are highly prevalent in Aboriginal and Torres Strait Islander people (30% to 40%), and contribute independently to cardiovascular risk.9

While diabetes greatly increases cardiovascular risk in Aboriginal and Torres Strait Islander people, the PBAC thought it reasonable to maintain a cholesterol threshold for lipid-modifying treatment in those without diabetes or other significant risk factors. They recognised that data on the clinical outcomes of lipid-modifying therapy in Aboriginal and Torres Strait Islander people are lacking and unlikely to become available.

Familial hypercholesterolaemia

Familial hypercholesterolaemia is a distinct genetic disorder characterised by hypercholesterolaemia that leads to cholesterol deposition in tissue — for example, tendon xanthoma. People with familial hypercholesterolaemia have a particularly high cardiovascular risk if untreated.10,11 The specific diagnostic criteria in the listing include DNA mutation, or tendon xanthomas in the patient or a first- or second degree relative. Since most people with familial hypercholesterolaemia have high cholesterol concentrations, it was thought that the specified thresholds would allow treatment of most people with this condition.

Lifestyle changes remain important

Diet and lifestyle interventions (including exercise and smoking cessation) are important in the management of cardiovascular risk, even when lipid-modifying therapy is used. Emphasise to patients that drug and non-drug therapy are likely to have independent benefits and that both are necessary to manage their condition.1

For high-risk groups, diet therapy must be started concurrently with PBS-subsidised lipid-modifying therapy.

For lower-risk groups, elevated lipid concentrations must be treated with diet and exercise therapy for 6 weeks before initiating PBS-subsidised lipid-modifying therapy. Start lipid-modifying treatment if lipid concentrations remain elevated after 6 weeks. Continue diet therapy concurrently with drug treatment.

The National Heart Foundation (NHF) recommends that all people should aim to participate in 30 minutes or more of moderate-intensity physical activity on most or all days of the week. See the NHF website www.heartfoundation.com.au for physical activity recommendations, such as Information for General Practice on Physical activity and Heart Disease.12

People with existing, well-compensated stable cardiovascular disease, should aim to undertake a similar amount of physical activity over time. Recognising that this is rarely achieved, the NHF physical activity algorithm for people with stable cardiovascular disease provides a step-by-step guide to evaluating existing activity and capability.13 This guide recommends the use of motivational interviewing techniques to gradually increase physical activity.

GPs can use chronic disease management plans to refer eligible patients to accredited dietitians and exercise physiologists. Up to 5 eligible allied health services visits per 12 month period will be reimbursed by Medicare. See Chronic Disease Management (CDM) Medicare Items (new from 1 July 2005).14

Use risk calculators as a guide to risk in primary prevention

Cardiovascular risk calculators based on epidemiological studies are often used to determine an individual’s risk of a cardiovascular event within a specified time frame. Risk factors that are taken into account include age, sex, cholesterol concentration, smoking status and hypertension. A calculator commonly used in Australia is the New Zealand cardiovascular risk calculator, based on data from the US Framingham population.

These calculators provide a guide to risk but may not accurately estimate risk for some groups — for example because of differences between the base population and the Australian population. In particular, the New Zealand Cardiovascular risk calculator is not accurate for predicting risk in1

  • people who have experienced a cardiovascular event
  • people aged >70 years
  • Aboriginal or Torres Strait Islander people
  • people with very high blood pressure (systolic blood pressure > 180 mmHg) or very high cholesterol concentration (total cholesterol > 8.0 mmol/L)
  • familial hypercholesterolaemia (see Familial hypercholesterolaemia)
  • atrial fibrillation
  • known kidney disease or impairment.

Apart from the above groups of people, it is acceptable to continue to use Framingham-based risk calculators until an Australia-specific calculator is available.15 In making its decisions about cardiovascular risk in the Australian population, the PBAC took account of large epidemiological studies and trials from abroad, as well as local disease incidence information (e.g. ANDIAB).

Authority requirements for ezetimibe preparations have changed

Ezetimibe preparations are not currently included in the PBS statement for lipid-lowering drugs. However, authority requirements for these drugs are linked to eligibility for statins — hence the Authority requirements have been further defined to account for high-risk patients who can receive lipid-modifying therapy at any concentration of cholesterol.

Patients with one of the medical conditions specified in the PBS listing can be prescribed ezetimibe (Ezetrol) or ezetimibe with simvastatin (Vytorin) because of inadequate control with a statin. In such patients, cholesterol must have remained inadequately controlled after 3 months’ statin therapy at 40 mg or more, in conjunction with diet and exercise. Inadequate statin control is defined according to PBS eligibility:

  • for people who can receive statins at any cholesterol concentration (Table 1), inadequate control is defined as total cholesterol > 4 mmol/L.
  • for people in whom a cholesterol threshold is required for PBS subsidy (Table 2), cholesterol concentrations must remain above that threshold.

Guidelines on lipid management

This review has described changes in the PBS criteria, which determine eligibility for PBS-subsidised treatment based on population estimates of risk, but are not a guideline for individual treatment.

For more information about lipid management consult the relevant guidelines; some examples are listed below.

Lipid Management

National Heart Foundation of Australia and the Cardiac Society of Australia and New Zealand. Position statement on lipid management — 2005.

http://www.heartfoundation.com.au/index.cfm?page=40

Therapeutic guidelines: Cardiovascular, 2003.

Aboriginal and Torres Strait Islander people

National Aboriginal Community Controlled Health Organisation. Evidence base to a preventive health assessment in Aboriginal and Torres Strait Islander peoples. Royal Australian College of General Practitioners, 2005.

http://www.racgp.org.au/guidelines/nationalguide

Diabetes Mellitus

National Health and Medical Research Council. National evidence based guidelines for the management of type 2 diabetes mellitus. Part 7: Lipid control in type 2 diabetes. http://www.nhmrc.gov.au/publications/synopses/di7todi13syn.pdf

Familial hypercholesterolaemia

The Cardiac Society of Australia and New Zealand. Guidelines for the diagnosis and management of familial hypercholesterolaemia, 2005. http://www.csanz.edu.au/guidelines/practice/Familial_hypercholesterolaemia.pdf.

References

  1. National Heart Foundation of Australia and the Cardiac Society of Australia and New Zealand. Position statement on lipid management — 2005. Heart Lung and Circulation 2005;14:275–91. http://www.heartfoundation.com.au
  2. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:7–22. [PubMed]
  3. Holman R. UK Prospective Diabetes Study (UKPDS). Oxford: Diabetes Trial Unit, University of Oxford, 2006. http://www.dtu.ox.ac.uk/index.php?maindoc=/ukpds/ (accessed 28 Nov 2006).
  4. Heart Protection Study Collaborative Group. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20 536 people with cerebrovascular disease or other high-risk conditions. Lancet 2004;363:757–67. [PubMed]
  5. Diabetes Trial Unit, The Oxford Centre for Diabetes Endocrinology and Metabolism. UKPDS Risk Engine. Oxford: Diabetes Trials Unit, 2006. http://www.dtu.ox.ac.uk/index.php?maindoc=/riskengine/ (accessed 15 Jan 2007).
  6. Collins R, Armitage J, Parish S, et al. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 2003;361:2005–16. [PubMed]
  7. Statins for primary prevention in type 2 diabetes. Drug Ther Bull 2006;44:57–60. [PubMed]
  8. Australian Institute of Health and Welfare. Heart, stroke and vascular diseases — Australian facts 2004. AIHW Cat. No. CVD 27. Canberra: AIHW and National Heart Foundation of Australia, 2004.
  9. National Aboriginal Community Controlled Health Organisation. Evidence base to a preventive health assessment in Aboriginal and Torres Strait Islander peoples. South Melbourne: Royal Australian College of General Practitioners, 2005. http://www.racgp.org.au/guidelines/nationalguide (accessed 28 Nov 2006).
  10. Burnett JA, Ravine D, van Bockxmeer F, et al. Familial hypercholesterolaemia: a look back, a look ahead. Med J Aust 2005;182:552–3.
  11. The Cardiac Society of Australia and New Zealand. Guidelines for the diagnosis and management of familial hypercholesterolaemia. 2005. http://www.csanz.edu.au/guidelines/practice/Familial_hypercholesterolaemia.pdf (accessed 28 Nov 2006).
  12. Heart Foundation NSW Division. Information for General Practice on Physical activity and Heart Disease. National Heart Foundation, 2004. http://www.heartfoundation.com.au/downloads/Final_physical_activity_and_heart_disease_low_Res.pdf (accessed 22 Jan 2007).
  13. National Heart Foundation of Australia. National Heart Foundation of Australia physical activity recommendations for people with cardiovascular disease. Canberra: National Heart Foundation of Australia, 2006. http://www.heartfoundation.com.au/downloads/PAR4CVD_FullRecs_06_Jan_final.pdf (accessed 13 November 2006).
  14. Chronic Disease Management (CDM) Medicare Items (new from 1 July 2005). Australian Government Department of Health and Ageing, 2004. http://www.health.gov.au/internet/wcms/Publishing.nsf/Content/pcd-programs-epc-chronicdisease (accessed 22 Jan 2007).
  15. National Vascular Disease Prevention Alliance (Diabetes Australia, Kidney Health Australia, National Heart Foundation of Australia and National Stroke Foundation of Australia). Consensus statement for the prevention of vascular disease. Aust Fam Physician 2004;33:235–9. http://www.kidney.org.au/assets/documents/NVDPA%20consensus%20statement.pdf