Lipid guidelines in the USA and Europe: A meeting of the minds?
Commentary by EAS Scientific writer Jane K. Stock
The 2018 American College of Cardiology (ACC) and American Heart Association (AHA) Cholesterol Guidelines1 were the headline act at the recent AHA Scientific Sessions, held in Chicago, Illinois, 10-12 November. The key question is: ‘How do these new guidelines compare with the 2016 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) Guidelines for Dyslipidaemia Management?’2 Lead author of the Joint European Guidelines, Professor Alberico L. Catapano (University of Milan, Italy) provided some insights.
The US and European guidelines share some common ground. Both agree that low-density lipoprotein cholesterol (LDL-C) is the primary focus for intervention; indeed, the totality of evidence establishes LDL C as causal for atherosclerotic cardiovascular disease (ASCVD).3 Findings from genetic studies reinforce this, showing the beneficial impact on lifetime cardiovascular risk associated with lifelong exposure to lower LDL-C levels.4 The USA Cholesterol Guidelines reiterate this by stating: ‘The more LDL-C is reduced on statin therapy, the greater will be the subsequent risk reduction.’
Published 2 years after the 2016 ESC/EAS Joint Guidelines, the 2018 US Guidelines had the opportunity to consider updated evidence for non-statin therapies, including data from randomized controlled trials (IMPROVE-IT with ezetimibe5 and ODYSSEY OUTCOMES and FOURIER with the PCSK9 monoclonal antibody therapies, alirocumab and evolocumab, respectively),6,7, meta-analyses and longer-term safety data. Despite this, the US Guidelines have been cautious in their recommendations. The focus is on patient characteristics in these trials, similar to the approach taken in the 2013 US Cholesterol Guidelines.8 Data from subgroup analyses of FOURIER in individuals with ASCVD affecting multiple vascular territories including peripheral artery disease, and with recurrent events,9,10 has been the basis for introducing a very high risk ASCVD category. This is defined as patients with a history of recurrent ASCVD events or with multiple high-risk conditions (i.e. age ≥65 years, heterozygous familial hypercholesterolaemia [FH], previous coronary intervention, diabetes, hypertension, chronic kidney disease, smoking and/or a history of congestive heart failure).
LDL-C goals by stealth?
In these very high risk patients, the US Guidelines have considered stepwise addition of nonstatin therapy, ezetimibe then a PCSK9 inhibitor if LDL C is ≥70 mg/dL or 1.8 mmol/L despite maximally tolerated statin therapy. Yet one can question the terminology used in these recommendations (‘may be considered’), given definitive evidence from randomized controlled trials that further lowering of LDL-C levels with nonstatin therapy provides further reduction in cardiovascular events? Furthermore, why not consider the evidence from the total study population of the PCSK9 inhibitor trials rather than focusing on the subgroups? Indeed, this is the approach taken by a Joint ESC/EAS Task Force on the use of PCSK9 inhibitors, albeit with different LDL-C thresholds for consideration of initiation of a PCSK9 inhibitor (taking account of the cost of treatment).11
There is also a lack of consistency with other US lipid guidelines. Notably, the American Association of Clinical Endocrinologists and the American College of Endocrinology introduced the concept of ‘extreme risk’ in their guidelines to denote patients with progressive ASCVD, and/or diabetes mellitus, chronic kidney disease or FH at very high cardiovascular risk. In these individuals, this guideline group recommended an LDL-C goal of <55 mg/dL (1.4 mmol/L) when considering data from IMPROVE-IT and FOURIER.12 In these extreme risk patients, this Guideline Group recommended that a PCSK9 inhibitor might be considered after high-intensity statin therapy given the magnitude of LDL-C reduction required.
The US guidelines also use LDL-C thresholds for treatment decisions (initiating statin therapy or adding nonstatin therapy) in other patient groups including those with or without diabetes aged 40-75 years; and individuals with LDL-C ≥190 mg/dl (4.9 mmol/L). This might suggest the revival of ‘LDL-C goals’ by stealth. Providing further support for this viewpoint is the new emphasis on monitoring the LDL-C lowering response to treatment (not considered in the 2013 US guidelines). Such an approach makes sense as clinicians are treating a risk factor and therefore need guidance on how low to lower LDL-C. There is also recognition of statin-associated muscle symptoms (SAMS), first proposed by the EAS Consensus Panel,13 which further emphasizes the need to monitor patients.
Positives: imaging and lipoprotein(a) feature
There are some positives from the guidelines. First, as already mentioned, there are recommendations for monitoring the LDL-C lowering response. Second, there is reference to elevated lipoprotein(a) (≥50 mg/dL or ≥125 nmol/L) as a ‘risk-enhancing factor’, with indication for measurement if there is a family history of premature ASCVD. This is very much in line with the ESC/EAS Joint Guidelines. Recognition of lipoprotein(a) is highly pertinent given that there is now a novel antisense oligonucleotide to apolipoprotein(a) which has been shown in phase II trials to be highly efficacious with a favourable safety profile.14 These findings provide a rationale for testing the ‘lipoprotein(a) hypothesis’ – does reduction of elevated lipoprotein translate to reduction in cardiovascular events?
Third, the US Guidelines make reference to the use of coronary artery calcium (CAC) scoring in risk estimation, particularly in the context of intermediate risk where clinicians are uncertain whether patients would benefit from statin therapy. If individuals have a zero CAC score, the guidelines recommend that it is reasonable to withhold treatment, except in those individuals who are smokers, have diabetes, a strong family history of ASCVD or a chronic inflammatory condition, and then re-assess in 5-10 years. Statin therapy is recommended if the CAC score is 1 to 99 (for individuals aged ≥55 years), and ≥100 or ≥ the 75th percentile.
Do these 2018 ACC/AHA Cholesterol Guidelines reflect the 2018 evidence-base on LDL-C lowering therapy? Perhaps these guidelines may be seen as underwhelming, although there have been improvements to the 2013 guidelines, specifically with respect to consideration of other risk enhancing factors, monitoring LDL-C response, and approaches to add-on nonstatin therapy. We await the next edition of the ESC/EAS Joint Guidelines on Dyslipidaemia Management, due next year, for a proper comparison of where Europe and the USA stand on lipid management.
1. Grundy SM, Stone NJ, Bailey AL et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol. Circulation 2018; available at https://www.ahajournals.org/doi/abs/10.1161/CIR.0000000000000625
2. Catapano AL, Graham I, De Backer G et al. 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias. Eur Heart J 2016;37:2999-3058.
3. Ference BA, Ginsberg HN, Graham I 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;38:2459-72.
4. Ference BA, Robinson JG, Brook RD, Catapano AL, Chapman MJ, Neff DR, Voros S, Giugliano RP, Davey Smith G, Fazio S, Sabatine MS. Variation in PCSK9 and HMGCR and risk of cardiovascular disease and diabetes. N Engl J Med 2016;375:2144-2153
5. Cannon CP, Blazing MA, Giugliano RP, et al; for the IMPROVE-IT Investigators. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372:2387-97.
6. Sabatine MS, Giugliano RP, Keech AC et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713–22.
7. Schwartz GG, Steg PG, Szarek M et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med 2018;published online 7 November 2018. DOI: 10.1056.NEJMoa1801174.
8. Stone NJ, Robinson JG, Lichtenstein AH et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63(25 Pt B):2889-934.
9. Bonaca MP, Nault P, Giugliano RP et al. Low-density lipoprotein cholesterol lowering with evolocumab and outcomes in patients with peripheral artery disease: insights from the FOURIER Trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk). Circulation 2018;137:338-50.
10. Sabatine MS, De Ferrari GM, Giugliano RP et al. Clinical benefit of evolocumab by severity and extent of coronary artery disease. Circulation 2018;138:756-66.
11. Landmesser U, Chapman MJ, Stock JK et al. 2017 Update of ESC/EAS Task Force on practical clinical guidance for proprotein convertase subtilisin/kexin type 9 inhibition in patients with atherosclerotic cardiovascular disease or in familial hypercholesterolaemia. Eur Heart J 2018;39:1131-43.
12. Jellinger PS, Handelsman Y, Bell DS, et al. American Association of Clinical Endocrinologists and American College of Endocrinology Guidelines for Management of Dyslipidemia and Prevention of Atherosclerosis. Endocr Pract 2017;23(Suppl 2):1-87.
13. Stroes ES, Thompson PD, Corsini A et al. Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Eur Heart J 2015;36:1012-22.
14. Tsimikas S et al. Safety and efficacy of AKCEA-APO(a)-LRx to lower lipoprotein(a) levels in patients with established cardiovascular disease: a Phase 2 dose-ranging trial. Abstract 19497, 2018 American Heart Association Scientific Sessions, 10-12 November, Chicago, USA.