Lowering the threshold for primary prevention with statins

John is a 62-year-old male who has completed his blood test for his cardiovascular risk assessment and appointment. He is a plumber, married with two adult children and two grandchildren, and tends to only see you when he has an injury, which is not often.

John’s five-year cardiovascular disease (CVD) risk is 7 per cent according to The Absolute CVD Risk/Benefit Calculator (cvdcalculator.com), using the New Zealand PREDICT risk equation. His total cholesterol to high-density lipoprotein (HDL) cholesterol ratio is 6.1 due to a low HDL cholesterol level of 0.9mmol/L. His low-density lipoprotein (LDL) cholesterol level is high at 4.2mmol/L.

Since the initial cardiovascular risk tables were developed by Aotearoa New Zealand’s epidemiologist Rod Jackson, we have altered our thinking about treating cardiovascular risk.

Initially, statins were relatively expensive medicines, so use was restricted to secondary prevention and very-high-risk primary prevention. This was a cost-effectiveness decision to target those people at greatest risk, although statins are effective even at lower cardiovascular risk. The studies at the time looked at total cholesterol and LDL cholesterol levels, rather than total cardiovascular risk, and found that any LDL reduction was beneficial.

By 2018, the new Aotearoa New Zealand guidelines, Cardiovascular Disease Risk Assessment and Management for Primary Care, meant that not only did we have a country-specific calculator (PREDICT) but statins were considerably less expensive; hence, the lowering of the threshold for treatment.

The Ministry of Health’s 2018 guidelines recommend we should discuss the use of a statin with people who have a five-year cardiovascular risk of 5 to 15 per cent, particularly those in the higher end of that spectrum.¹

While cardiovascular risk is an excellent tool to assist with treatment decisions because it encourages us to focus holistically and treat all risk factors, the treatment of dyslipidaemia itself is changing. There had always been discord between using the total cholesterol to HDL cholesterol ratio as a trigger for treatment and then using the LDL cholesterol level as the target for treatment.

The UK’s National Institute for Health and Care Excellence (NICE) guidance previously recommended that people with a 10-year risk of a cardiovascular event of more than 10 per cent (approximately 5 per cent five-year risk) be offered a statin. That threshold remains in the 2023 guidance, but it also recommends a more person-centred approach by considering a statin for people with a 10-year cardiovascular risk of “less than 10 per cent if they have an informed preference for taking a statin or there is concern that risk may be underestimated”.²

The guidance states that if more people took statins, there would be a greater reduction in CVD events – it is estimated that for every 1000 people with a 5 per cent 10-year risk who take a statin, the statin will prevent approximately 20 people from having a cardiovascular event in this time; and for those with a 10 per cent 10-year risk, the statin will prevent about 40 people from having a cardiovascular event.³

Applying this to the New Zealand environment is perhaps a matter of changing our perception of when to more actively advocate for the introduction of a statin. A hangover from the 1990s and early 2000s is the perception that we should wait until the five-year cardiovascular risk is closer to 10 per cent before starting a statin, but with the new evidence, having a more intense discussion when the five-year cardiovascular risk is around 5 per cent would be recommended. In particular, this is important for younger people and those with higher LDL cholesterol levels (eg, over 4.0mmol/L).

Importantly for Māori and Pacific peoples, the risk of CVD is higher than for Europeans, and CVD occurs at a younger age, so the implications of starting a statin early are even greater.

Age is a strong driver of cardiovascular risk (see table), and there is concern that cardiovascular risk calculators underestimate the lifetime risk of a cardiovascular event. Consequently, the European Society of Cardiologists (ESC) guidelines suggest different thresholds for the treatment of cardiovascular risk factors, including statin initiation, at different ages (risk thresholds for considering treatment are lower for younger people).⁴

This indicates that we should not wait until age pushes the person to higher risk categories but start treatment earlier. A group this is particularly pertinent for is those with mental health conditions, who are usually younger.

At the other end of the scale are those people who are older. Despite the ESC guideline for increasing the threshold for treatment with age, it is important to recognise the benefits of treating older people. Depending on the study, primary prevention with statins still results in a 16 to 39 per cent relative reduction in major cardiovascular events for people aged 65 to 75. The evidence is less clear for those over age 75, especially concerning mortality benefit.⁵

The aim of primary prevention is to reach old age, and the definition of old age is flexible. Decisions should consider the person’s frailty, life expectancy and perspective towards taking medicines.

With more potent statins and other potent LDL cholesterol-lowering medicines available, there is greater clarity around whether it is the LDL cholesterol lowering that is beneficial or whether it is the pleiotropic effects of statins, such as anti-inflammatory effects. It seems the answer is both. There are pleiotropic effects, but LDL cholesterol lowering to a target level, rather than just proportionally, is important.

There is increasing evidence that while we had recognised early use of statins reduces the progression of atherosclerotic plaques, more potent statins can help stabilise plaque. Further, there is potentially plaque regression with the newer monoclonal antibody proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, which lower LDL cholesterol into the 1–2mmol/L range. This has helped drive the focus on more intensive LDL cholesterol reduction.

The Cardiac Society of Australia and New Zealand and the New Zealand Society for the Study of Diabetes recommend lowering LDL cholesterol to less than 1.4mmol/L for secondary prevention and for those at high cardiovascular risk (>15 per cent five-year risk).^6,7

Extrapolating for primary prevention at <15 per cent five-year risk, it is reasonable to consider that the higher the cardiovascular risk, the lower the LDL cholesterol target. Aiming for an LDL cholesterol level of <2mmol/L is reasonable, and if a cholesterol-lowering medicine is initiated, ensure planned follow-up, with the target being reached so that treatment is meaningful.

With the less definite thresholds for initiation of a statin according to five-year cardiovascular risk, and allowing for consideration of age, LDL cholesterol level and personal preferences, it is challenging to provide quantified information to help the decision.

Broadly taking the calculated cardiovascular risk and using a relative risk reduction of 20 to 25 per cent will help provide a number needed to treat (NNT) for five years to prevent one cardiovascular event. For John, this would be a 25 per cent reduction from 7 per cent (ie, an absolute risk reduction of approximately 1.8 per cent), so an NNT for five years of approximately 55 – although it depends on the intensity of statin used (see table). This can help people understand the benefit. Other methods for discussing benefits and risks with people are:

• The New Zealand PREDICT equation on the interactive Absolute CVD Risk/Benefit Calculator (cvdcalculator.com). This has smiley faces and can show the effect of different treatments, such as blood pressure lowering.
• My Heart Check from the Heart Foundation (myheartcheck.org.nz), although this tool can be confronting for people whose calculated heart age is much higher than their chronological age.

You discuss the initiation of a statin with John, providing the NNT to prevent a cardiovascular event within five years. You also comment on his relatively high LDL cholesterol level, which is likely to accumulate, being an added lifetime risk that may be underestimated. With his agreement, you initiate atorvastatin 40mg daily, warning John of potential adverse effects, although recent studies have shown these to be uncommon. Your target LDL cholesterol level will be 2mmol/L or less.

This case study does not represent an identifiable person

Linda Bryant is a pharmacist prescriber at Newtown Union Health Service and Porirua Union and Community Health Service, Wellington