In view of the emergence of a substantial body of evidence in recent years, lipid management guidelines from European Society of Cardiology (ESC), European Atherosclerosis Society (EAS) (2019)1, American Heart Association (AHA) and American College of Cardiology (ACC) (2018)2 have undergone significant updates since the previous recommendations in 2016 and 2013, respectively. The establishment of goal directed medical therapy with lower low-density lipoprotein cholesterol (LDL-C) thresholds and guidelines on non-statin therapy use are the most significant updates between previous and current guidelines.

By Dr Natalie Koh, Consultant, Department of Cardiology

The key to managing lipids is first understanding the patient’s cardiovascular risk and then tailoring treatment to reach risk-appropriate LDL-C thresholds. Based on the treatment goals, the prescribing physician needs to decide the intensity of statins to initiate treatment with, and what non-statin therapy may be indicated if goals cannot be met despite maximal tolerated statin therapy.

Defining Cardiovascular Risk

The ESC and EAS define cardiovascular risk estimation as part of a continuum ranging from very high risk, high risk, moderate risk and low risk. The cut-off points that were used to define risk are in part, both arbitrary and based on evidence from clinical trials. The 2018 definition by AHA and ACC divides the
population into primary and secondary prevention cohorts, and the secondary prevention cohort is further divided into high risk versus very high risk. Very high risk cohorts have a history of multiple major atherosclerotic cardiovascular disease (ASCVD) events or one major ASCVD event and multiple high-risk conditions.

LDL-C Treatment Goals and Thresholds

The 2019 ESC and EAS guidelines recommend lowering LDL-C to as low a level as possible, because evidence suggests that lowering LDL-C beyond the goals previously set in 2016 is associated with fewer ASCVD events. Compared to the 2016 guidelines, the LDL-C threshold for the very high risk cohort is now < 1.4 mmol/L AND a ≥ 50% reduction from baseline (see Table 1).

Table 1: Comparison of ESC/EAS 2016 vs 2019 guidelines1

The ACC and AHA 2018 guidelines recommend risk stratification amongst primary prevention cohorts (see Table 2), and commencement of statins to reduce LDL-C by 30% to ≥49% in intermediate risk and ≥50% in high risk. In secondary prevention cohorts, the 2018 guidelines recommend targeting a reduction in LDL-C of 50% and if LDL-C is still ≥70mg/dL to consider adding ezetimibe in high-risk patients. For very high risk patients, upfront high intensity or maximal tolerated statins should be commenced and if LDL-C is still ≥70mg/dL on top of ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors should be considered.

Table 2: 2018 ACC/AHA Guidelines for primary prevention of ASCVD risk2

Lipid Treatment Options

The backbone of lipid lowering therapy remains statins. The general observation holds that high intensity statins lower LDL-C by a median of 50%, and moderate intensity statins lower LDL-C by a median of 30%. 

With the publication of IMPROVE-IT3, Fourier4 and Odyssey5 Trials, the use of non-statin therapy with proven cardiovascular benefit on top of maximal tolerated statin has been established and written into management guidelines.

Ezetimibe should be considered as an adjunct therapy for high to very high risk patients who do not reach LDL-C goals on high intensity or maximal tolerated statin therapy. The addition of PCSK9 inhibitors should be considered in the highest risk category if even an addition of ezetimibe does not achieve goals. The ESC/EAS 2019 guidelines further recommend that in statinintolerant patients, PCSK9 inhibitors may also be considered on top of ezetimibe.

Treatment Practicalities

With established LDL-C targets to achieve, physicians now have clearer treatment goals as opposed to previous “fire and forget” advice from older guidelines.

It is relatively more straightforward to identify the high risk and very high risk cohorts by virtue of their co-morbidities and medical history. The difficulty with these cohorts is achieving stringent LDL-C targets which many doubt can be achieved by oral therapy alone, despite literature suggesting that Asians achieve LDL-C goals with lower doses of statins. Certainly, the threshold to add non-statin therapy like ezetimibe PCSK9 inhibitors on top of maximal tolerated statin therapy must now be lower, with increased physician awareness of its additional cardiovascular benefit in these cohorts. Having said that, significant challenge remains for initiating PCSK9 inhibitor therapy due to the injection administration and medication costs.

The initiation of lipid lowering therapy in the primary prevention cohort remains one that is more nuanced, and requires clinical judgement and perhaps adjunct investigations. The risk scores (ASCVD and the systematic coronary risk evaluation) applied in the guidelines may not be generalised across Asian cohorts, but an understanding of risk enhancers and tools such as the coronary artery calcium score per the ACC and AHA 2018 guidelines (see Table 2) is useful for further risk stratification and individualisation of LDL-C goals, and sets the stage for meaningful discussion with the patient on risks and benefits of treatment.

Key Takeaways

Given the multitude of lipid lowering drugs (both statin and non-statin) with proven cardiovascular benefit, medical professionals must consistently identify patients who will benefit most from intensive upfront treatment and maximal therapy, and commence treatment expediently. With a modern armamentarium of risk stratification tools such as coronary artery calcium scores, ankle-brachial index and other biochemical markers, medical professionals should seek more objective and precise measures of individual cardiovascular risk to decide on lipid lowering therapy and thresholds in the primary prevention of the disease. 

1 2019 Guidelines for the management of Dyslipidaemias: lipid modification to reduce cardiovascular risk: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). Eur Heart J 2019
2 2018 Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology Foundation/ American Heart Association Task Force on Clinical Practice Guidelines. JACC 2018 
3 IMProved Reduction of Outcomes: Vytorin Efficacy International Trial – IMPROVE-IT. The New England Journal of Medicine 2015
4 Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk – FOURIER. Am Heart J 2016
5 Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: rationale and design of the ODYSSEY Outcomes trial. Am Heart J 2014

This article is from Murmurs Issue 37 (May – August 2020). Click here to read the full issue.