A report on the Joint session of the EAS and the US National Lipid Association
How different – or similar – are European and US lipid guidelines?
This session discussed targets and therapeutic approaches in the two regions. You can view it on demand.
Targets: the EAS way versus the US way
The ‘EAS way’ is clearly reflective of the science, according to Professor Chris Packard (University of Glasgow, UK), In 2017, the EAS Consensus Panel statement conclusively established low-density lipoprotein (LDL) as causal for atherosclerotic cardiovascular disease (ASCVD) (1). Evidence from observational and genetic studies, as well as randomised controlled studies, demonstrated a relationship between LDL and ASCVD that was continuous and causal across the range of LDL cholesterol levels. Furthermore, in clinical trials there was a monotonic dose-response between LDL cholesterol lowering and clinical benefit, extending to the very low LDL cholesterol levels attained with PCSK9 inhibitors (2), with no apparent trade-off between safety and efficacy. The Cholesterol Treatment Triallists Collaboration (3) quantitated this relationship, showing that each 1 mmol/L reduction in LDL cholesterol translates to 22% lower cardiovascular risk. Overviewing results from clinical trials with statins, ezetimibe and PCSK9 inhibitors, all of which mediate LDL cholesterol reduction via increased LDL receptor-mediated clearance, it is clear that there is consistent reduction in coronary heart disease risk per unit decrease in LDL cholesterol.
This evidence provided a scientific framework for setting therapeutic LDL cholesterol goals. The landmark outcomes studies with PCSK9 inhibitors (4,5) supported lowering LDL cholesterol goals to more stringent levels in the 2019 ESC/EAS guidelines. Furthermore, a second goal of at least 50% reduction from baseline LDL cholesterol was added for high and very high-risk patients. Thus, the scientific evidence supports a high-risk, high-benefit approach in deciding who should receive combination therapy, in line with a recent pragmatic proposal (6). Individuals at highest risk and with the highest LDL cholesterol levels on statin clearly merit the addition of highly efficacious non-statin LDL cholesterol lowering therapy.
Finally, while there are currently no goals for triglyceride and HDL cholesterol, remnant-associated risk is encapsulated within the secondary targets of non-HDL cholesterol and apolipoprotein B.
Professor Carl E. Orringer (University of Miami Miller School of Medicine, Florida, USA) responded with targets and goals the US way. In 2015 (6), the National Lipid Association (NLA) recommended patient-centred management of dyslipidaemia, with treatment goals that aimed to ensure that the intensity of treatment was matched to absolute risk. To bridge gaps between the 2013 ACC/AHA guidelines and the 2015 NLA guidelines, the use of ‘lipoprotein thresholds’ was agreed to aid clinical decision making for the necessity of non-statin therapy (7). These thresholds were based on both percent LDL cholesterol reduction achieved and absolute LDL cholesterol values associated with clinical cardiovascular benefit.
In the 2018 ACC/AHA guidelines (8), high risk patients were further categorised as very high risk, based on the presence of ASCVD, and additional ‘risk enhancers’, which included lipoprotein(a) >50 mg/dL among other factors. This allowed the guidelines to introduce the concept of an LDL threshold for addition of nonstatin therapy, first for ezetimibe and then a PCSK9 inhibitor.
Take home message: The European and US guidelines both agree on the key targets- LDL cholesterol and non-HDL cholesterol. While the terminology may differ, both have a consistent strategy for considering add-on non-statin therapy in high and very high-risk patients. Furthermore, both agree that there are no safety concerns regarding very low LDL cholesterol levels.
Therapeutic approaches: the EAS way versus the US way
According to Professor Alberico Catapano (University of Milan, Italy), four key drivers underpin the EAS approach to therapy: 1) the evidence (discussed above); 2) trials of LDL cholesterol lowering showing that the relative risk reduction is proportional to the absolute risk reduction; 3) support that lower LDL cholesterol is better; and 4) a strategy for intensity of LDL cholesterol lowering based on risk, irrespective of cause. These four drivers led to lower LDL cholesterol goals in very-high, high and moderate risk patients in the 2019 guidelines, and for the first two categories, the inclusion of a second goal of more than 50% reduction from baseline in LDL cholesterol to ensure sufficiently robust prevention of cardiovascular events.
Maximally tolerated high intensity statin is clearly foundational, with add-on therapy with ezetimibe and a PCSK9 inhibitor in order to attain LDL cholesterol goals in high and very high-risk patients. The guidelines also emphasise the importance of secondary goals – non-HDL cholesterol and apolipoprotein B – especially in those patients with cardiometabolic disease, including diabetes and metabolic syndrome.
For the USA way for primary prevention, Dr Christie Ballantyne (Baylor College of Medicine, Houston, Texas) focused on a heart-healthy lifestyle, early and aggressive treatment of high LDL cholesterol in patients with high LDL cholesterol (≥190 mg/dL) and with diabetes, and estimation of ASCVD risk.
For secondary prevention patients, a key question is who should receive non-statin therapy. Patients at very high risk (with multiple events or with one event and risk enhancers) with high LDL cholesterol levels on statin are one key category, with add-on ezetimibe and, if needed a PCSK9 inhibitor, based on LDL cholesterol thresholds. The cost of PCSK9 inhibitor therapy is clearly a consideration.
Take home message: Despite some disparities in terminology, ‘Lower is better’ underpins both the EAS and US approaches for managing high and very high-risk patients. The European guidelines have, however, taken a more pragmatic step in further lowering LDL cholesterol goal in very high-risk patients, especially those with recurrent cardiovascular events.
2019 EAS/ESC guidelines: Mach F, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020;41:111-188.
- Ference BA, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J 2017;38:2459-2472.
- Giugliano RP, et al. Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial. Lancet 2017;390:1962-1971.
- Collins R, et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet 2016;388:2532-2561.
- Sabatine MS, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713-1722.
- Schwartz GG, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med;379:2097-2107.
- Jacobson TA, et al. National lipid association recommendations for patient-centered management of dyslipidemia: part 1–full report. J Clin Lipidol 2015;9:129-69.
- Lloyd-Jones DM, et al. 2017 Focused update of the 2016 ACC Expert Consensus Decision Pathway on the role of non-statin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk: a report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol 2017;70:1785-1822.
- Grundy SM, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2019;73:e285-e350.