Appropriate primary prevention of cardiovascular disease: does this mean more or less statin use?
Jane Smith, Associate professor, General Practice, Faculty of Health Science and Medicine, Centre for Research in Evidence-based Practice, Bond University, Gold Coast, Queensland

Summary

Treatment with HMG-CoA reductase inhibitors, commonly known as statins, is beneficial for people at high risk of a cardiovascular event. However, guidelines recommend against routine statin treatment for those with a lower risk.They also recommend waiting until after 45 years of age to assess cardiovascular risk in healthy individuals. Aboriginal and Torres Strait Islander people should be assessed from age 35 years.These recommendations are based on current evidence of who is more likely to benefit from statin treatment.

Key words: antilipidaemic drugs, cholesterol, HMG-CoA reductase inhibitors

Aust Prescr 2011;34:169-72

Introduction

Cardiovascular disease is a common problem causing 16% of the total disease burden, second to cancer. The mortality from cardiovascular disease has decreased by at least 80% in the last 50 years, mostly before the introduction of statins (HMG-CoA reductase inhibitors). Although Australians are living longer, greater rates of physical inactivity, obesity and diabetes all threaten this trend.1

The absolute risk of developing cardiovascular disease is predictable using risk calculation tools.2 Statins are known to reduce this risk in people with existing ischaemic cardiovascular disease, or those at high risk of developing it – defined as more than 15% risk of an event in five years. However it is less clear whether people with a lower cardiovascular risk, benefit from statins.

Statin use

The number of patients diagnosed with high cholesterol has doubled between 2004 and 2009.3 The focus on single risk factors like cholesterol translates to 27% of adult general practice patients being managed for cholesterol4 – three-quarters of them are treated with statins.

Patients and health providers alike tend to focus on cholesterol, perhaps because it is an easy target to test and treat. A possible consequence of this is that statins are the most prescribed of all drugs both in quantity and cost on the Pharmaceutical Benefits Scheme (PBS). There are three individual statins in the top 10 of all prescribed drugs – atorvastatin, simvastatin and rosuvastatin.5 Suggestions have been made about both under- and over-prescribing of statins in Australia. Women are far more likely to be treated with statins relative to their risk for cardiovascular disease than men, with the exception of men in the highest socioeconomic group. Rural people are less likely to be treated with a statin.6

Cardiovascular risk

The term cardiovascular risk refers to the risk of ischaemic disease defined as acute coronary events, angina, stroke, transient ischaemic events, and peripheral vascular disease with or without fatal outcomes. There are multiple modifiable factors that influence the risk of developing cardiovascular disease (Box 1). Modifying these factors can improve morbidity and mortality and includes lifestyle factors such as increasing physical activity and cardiorespiratory fitness, and not smoking.7,8 If these interventions do not sufficiently reduce the risk of cardiovascular disease, pharmacological interventions may need to be considered.

Generally people under 45 years are likely to have a low risk of cardiovascular disease, as age is one of the biggest determinants of risk, and multiple risk factors are not common in younger people.

A family history of high cholesterol affects 5–20% of the population, depending on how one defines high cholesterol.

This is sometimes confused with familial hypercholesterolaemia (LDL >4.9 mmol/L usually with tendon xanthoma) which affects 1 in 500 (0.2%) people.9 This is a high risk condition and results in coronary heart disease or stroke at a young age (under 60 years).

Box 1
Modifiable risk factors for cardiovascular disease

Smoking

High blood pressure

Elevated cholesterol (total or low density lipoprotein)

Decreased high density lipoprotein cholesterol

Diabetes

Obesity (large waist measurement, high body mass index)

Lifestyle (minimal exercise, poor nutrition, high stress, excess alcohol)

Risk calculation

Calculating absolute risk using Framingham data adapted for Australia is well validated, based on multiple factors including cholesterol levels, but is underused.2 These tools tend to overestimate the risk in those of European descent but underestimate the risk in high risk groups such as Aboriginal and Torres Strait Islander, Pacific Islander or Indian people. Easy-to-use online tools for calculating cardiovascular risk are shown in Box 2.

Table 1 shows who should have a cardiovascular risk calculation. Conversely, some patients' risk is high enough to not need any risk calculation. These are patients who have had a previous cardiovascular event. It also includes some patients with hypercholesterolaemia, diabetes, hypertension or moderate to severe chronic kidney disease (Box 3).

Box 2
Online tools for calculating cardiovascular risk

www.heartfoundation.org.au/information-for-professionals/Clinical-Information/Pages/absolute-risk.aspx
[cited 2011 Nov 7]

www.racgp.org.au/redbook/app3
[cited 2011 Nov 7]

National Vascular Disease Prevention Alliance: Australian absolute cardiovascular disease risk calculator. 2010.
www.cvdcheck.org.au

[cited 2011 Nov 7]

www.knowyournumbers.co.nz/heart-age-forecast.aspx
[cited 2011 Nov 7]

Other sources of the same risk calculators are in the Royal Australian College of General Practitioners primary care sidebar and some pathology laboratory reports


Box 3
People at high risk of a cardiovascular event (>15% in the next 5 years) who therefore do not require cardiovascular risk calculation2
Characteristics

Known cardiovascular disease

Diabetes with microalbuminuria

(>20 microgram/minute or urinary albumin:creatinine ratio >2.5 mg/mmol for males and >3.5 mg/mmol for females)

Diabetes >60 years

Moderate or severe chronic kidney disease

(eGFR <45 mL/minute/1.73 m2)

Familial hypercholesterolaemia

Serum cholesterol >7.5 mmol/L

Systolic blood pressure >180 mmHg or diastolic >110 mmHg

eGFR estimated glomerular filtration rate

Recommendations for cholesterol testing

About 8% of adult patient encounters in general practice involve cholesterol testing but evidence suggests most of these tests do not result in any benefit to patients.3,10 The Royal Australian College of General Practitioners guidelines for preventive activities in general practice recommend testing adults over 45 years of age for their cholesterol levels every five years (or from 35 years if Aboriginal and Torres Strait Islander).11,12 Similar recommendations are given by the National Vascular Disease Prevention Alliance (Table 1).2

Table 1
Who needs risk calculation for cardiovascular disease?2
Patient characteristics Recommendation *
All adults 45–75 years of age B (strong)
Aboriginal and Torres Strait Islander people from 35 years of age C (medium )
Diabetes <60 years C (medium)
Overweight or obese D (weak)
* Based on the National Vascular Disease Prevention Alliance guidelines
National Health and Medical Research Council gradings:
  • ABody of evidence can be trusted to guide practice
  • BBody of evidence can be trusted to guide practice in most situations
  • CBody of evidence provides some support for recommendation but care should be taken in its application
  • DBody of evidence is weak and recommendation must be applied with caution

Evidence

Most of the evidence about the effect of statins in primary prevention is based on treatment of high-risk males aged 55–65 years.13 There is little evidence about benefit in younger age groups. In those at high risk, statins lower ischaemic event rates and all-cause mortality, and are cost-effective. This has not been shown in lower-risk populations.14

Systematic reviews of trials differ in their conclusions about the benefits of statins in patients who do not have a high risk. When patients with prior cardiovascular disease are excluded, there is no evidence of benefit from statin therapy on all-cause mortality.13 This suggests that caution should be used when recommending statins for primary prevention of cardiovascular disease in those at low risk (that is with a risk of cardiovascular disease less than 2% in one year) because of limited benefit and a potential for harm (Table 2).15,16

In those with moderate to severe chronic kidney disease, statin treatment reduces cardiovascular events but not overall mortality.17 However, statin treatment of those with less severe chronic kidney disease appears to reduce cardiovascular events and overall mortality.18

Table 2
Benefits and harms associated with statin treatment over five years in patients at high risk of cardiovascular disease16
Event Men Women
Number needed to treat
Cardiovascular disease 33 37
Number needed to harm
Myopathy 91 259
Liver dysfunction 142 136
Acute renal failure 346 434
Cataract 52 33
† Patients had a 20% or more risk of cardiovascular event over 10 years

PBS listing

The PBS general statement for using lipid-lowering drugs defines patients at risk who would be expected to benefit from statin therapy. The wording is intended to mirror the absolute cardiovascular disease risk calculation, but is an imperfect match.

Conclusion

It is likely that we are over-prescribing statins to low-risk patients. A focus on single risk factors such as high cholesterol promotes statin treatment. This will not benefit patients unless they have a high risk of cardiovascular disease, and it could result in harm. It is appropriate to assess absolute cardiovascular risk in people aged over 45 years (or from 35 years if Aboriginal and Torres Strait Islander) using tools that integrate multiple risk factors.

References

  1. Australian Institute of Health and Welfare. Australia's health 2010. Canberra: AIHW; 2010.
  2. National Vascular Disease Prevention Alliance evidence- based practice guidelines for the assessment of absolute cardiovascular disease risk. Canberra: National Health and Medical Research Council; 2009 .
  3. Britt H, Miller GC, Charles J, Henderson J, Bayram C, Valenti L, et al. General practice activity in Australia 1999-00 to 2008-09: 10 year data tables. Cat. no. GEP 26. Canberra: Australian Institute of Health and Welfare; 2009.
  4. Britt H, Miller GC, Charles J, Valenti L, Fahridin S, Pan Y, et al. General practice activity in Australia 2009–10. General practice series no. 27. Cat. no. GEP 27. Canberra: Australian Institute of Health and Welfare; 2010.
  5. Top 10 drugs. Aust Prescr 2011;34:172.
  6. Stocks N, Ryan P, Allan J, Williams S, Willson K. Gender, socioeconomic status, need or access? Differences in statin prescribing across urban, rural and remote Australia. Aust J Rural Health 2009;17:92-6 .
  7. Mitchell JA, Bornstein DB, Sui X, Hooker SP, Church TS, Lee CD, et al. The impact of combined health factors on cardiovascular disease mortality. Am Heart J 2010;160:102-8 .
  8. Sui X, LaMonte MJ, Blair SN. Cardiorespiratory fitness and risk of nonfatal cardiovascular disease in women and men with hypertension. Am J Hypertens 2007;20:608-15.
  9. Civeira F, Ros E, Jarauta E, Plana N, Zambon D, Puzo J, et al. Comparison of genetic versus clinical diagnosis in familial hypercholesterolemia. Am J Cardiol 2008;102:1187-93.
  10. Doll H, Shine B, Kay J, James T, Glasziou P. The rise of cholesterol testing: how much is unnecessary. Br J Gen Pract 2011;61:e81-8 .
  11. Harris M, Bennett J, Del Mar C, Fasher M, Foreman L, Furler J, et al. Guidelines for preventive activities in general practice. 7th ed. Melbourne: The Royal Australian College of General Practitioners; 2009 .
  12. Harris MF, Bailey L, Snowdon T, Litt J, Smith JW, Joyner B, et al. Developing the guidelines for preventive care – two decades of experience. Aust Fam Physician 2010;39:63-5.
  13. Ray KK, Seshasai SR, Erqou S, Sever P, Jukema JW, Ford I, et al. Statins and all-cause mortality in high-risk primary prevention: a meta-analysis of 11 randomized controlled trials involving 65,229 participants. Arch Intern Med 2010;170:1024-31 .
  14. Greving JP, Visseren FL, de Wit GA, Algra A. Statin treatment for primary prevention of vascular disease: whom to treat? Cost-effectiveness analysis. BMJ 2011;342:d1672 .
  15. Taylor F, Ward K, Moore TH, Burke M, Davey Smith G, Casas JP, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev 2011;1:CD004816 .
  16. Hippisley-Cox J, Coupland C. Unintended effects of statins in men and women in England and Wales: population based cohort study using the QResearch database. BMJ 2010;340:c2197.
  17. Strippoli GF, Navaneethan SD, Johnson DW, Perkovic V, Pellegrini F, Nicolucci A, et al. Effects of statins in patients with chronic kidney disease: meta-analysis and meta-regression of randomised controlled trials. BMJ 2008;336:645-51 .
  18. Navaneethan SD, Pansini F, Perkovic V, Manno C, Pellegrini F, Johnson DW, et al. HMG CoA reductase inhibitors (statins) for people with chronic kidney disease not requiring dialysis. Cochrane Database Syst Rev 2009;2:CD007784 .

Associate professor Smith is a member of the Editorial Advisory Committee of the Australian Medicines Handbook, member of the Advisory Editorial Panel of Australian Prescriber, and an author of the guidelines for preventive activities in general practice.

Self-test questions

The following statements are either true or false (click here for the answers)

1. Statins do not reduce overall mortality in people with severe renal impairment.

2. The National Vascular Disease Prevention Alliance recommends assessing the absolute cardiovascular risk in people over the age of 75.



First published online: December - 2011