Europe is an increasingly elderly society. In 2019, 14% of individuals in the European Union member countries were aged 65-79 years and about 6% were aged 80 years or more; over the next 20 years, the proportion aged at least 80 years is anticipated to more than double.1 This is highly relevant in the context of prevention strategies aimed at reducing the burden of atherosclerotic cardiovascular disease (ASCVD).
One of the major risk factors for ASCVD is low-density lipoprotein cholesterol (LDL-C).2,3 Yet, when to start, continue, or stop LDL-C lowering treatment in the elderly has been a recurring concern for clinicians. This uncertainty has persisted as the elderly are generally underrepresented in cardiovascular outcome trials.
The 2019 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines recommend treating elevated LDL-C in high-risk and very-high-risk individuals over 75 years but are more cautious in recommendations for those at lower-risk without ASCVD, reflecting the current evidence-base.4 Support for the use of statins in the elderly with ASCVD is conclusive, including findings from a meta-analysis of 28 trials by the Cholesterol Treatment Trialists’ Collaboration (CTTC), 5a retrospective analysis of the Catalan primary care database,6 and a meta-analysis of patients aged >65 years in 23 trials.7 In contrast, the CTTC meta-analysis showed no significant benefit from LDL-C lowering with a statin in older patients who were asymptomatic (i.e. primary prevention).5
Achieving the stringent LDL-C treatment targets for high-risk and very-high-risk patients usually involves the use of combination LDL-lowering therapy. This poses a key question: Do elderly secondary prevention patients with elevated LDL-C gain similarly from statin, either alone or in combination with non-statin therapy? While several subgroup analyses from randomized controlled trials of non-statin therapeutic approaches suggest benefit,8-12 further evaluation is needed.
This uncertainty was addressed in the latest meta-analysis from the CTTC.13 This was the largest to date, involving 21,492 individuals aged ≥75 years, predominantly with manifest ASCVD, in 29 trials of statin (54.7%, n=11,750), ezetimibe (28.9%, n=6,209), or PCSK9 inhibitor therapy (16.4%, n=3,533).13 Over a median follow-up of 2.2-6.0 years, treatment with an LDL-C lowering agent reduced the risk of major vascular events by 26% per 1.0 mmol/L decrease in LDL-C, with no significant difference compared with that observed in younger individuals. Importantly, the magnitude of clinical benefit per 1.0 mmol/L decrement in LDL-C levels did not differ significantly between statin and non-statin therapy. Incidentally, supplementary analyses showed no benefit from LDL-C lowering in elderly individuals without manifest vascular disease.13
There was also no evidence to indicate safety concerns with statin or non-statin therapy in the elderly, with no increase in the risk of cancer, or the risk of haemorrhagic stroke, new-onset diabetes or neurocognitive effects with non-statin therapy, compared with younger individuals.13 Other studies, such as the Patient and Provider Assessment of Lipid Management (PALM) registry, also report that LDL-C lowering treatment was similarly well tolerated in older and younger adults.14
Returning to the question of LDL-C lowering therapy in elderly primary prevention patients, Danish investigators evaluated the association between LDL-C and ASCVD risk in over 90,000 individuals in the Copenhagen General Population Study, a contemporary primary prevention population.15 The analysis specifically selected ‘healthy’ elderly individuals who were not on lipid lowering therapy and did not have ASCVD or diabetes at baseline. Overall, 15% – or one in six- were aged 70 years or more, and 3% were 80 years or older.
Across all age groups (from those aged 20-49 years to 80-100 years), there was a consistent increase in the relative risk of myocardial infarction or ASCVD per 1.0 mmol/L increase in LDL-C. However, the absolute risk was accentuated in those aged 70 years or more, compared with younger individuals, resulting in a much lower number needed to treat (NNT) to prevent one event.15 Based on their findings, the authors make a case for identifying and treating elevated LDL-C in elderly primary prevention patients.
Take home messages
The analysis from the Copenhagen General Population Study reaffirms the concept of cumulative LDL-C burden over the lifetime as a key determinant of ASCVD risk, with elderly individuals with higher LDL-C levels at higher absolute risk of ASCVD.4,15 Whether these individuals derive net benefit from LDL-C lowering therapy, however, is still unclear. The current CTTC analysis did not show a significant reduction in risk of vascular events per 1.0 mmol/L lowering of LDL-C in elderly primary prevention cohorts. 13Non-vascular effects from initiating LDL-C lowering therapy in elderly patients without ASCVD also need to be considered, given that the CTTC meta-analysis showed a lack of benefit from LDL-C lowering therapy on non-vascular mortality.13 The STAREE trial (A Clinical Trial of STAtin Therapy for Reducing Events in the Elderly; NCT02099123) in primary prevention patients aged 70 years and older will provide critical information to resolve these questions.
From a societal perspective, as resources available to healthcare systems become increasingly finite, preventive health strategies become even more important. With an aging population, ASCVD will become an increasing burden. Addressing current uncertainty regarding the benefit versus risk of treating elderly primary prevention patients with elevated LDL-C will have important impact for clinical practice, guidelines and wider society.
References
1. Eurostat. Population structure and ageing. Available at https://ec.europa.eu/eurostat/statistics-explained/index.php/Population_structure_and_ageing#The_share_of_elderly_people_continues_to_increase (Accessed 11 November 2020).
2. 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.
3. Borén J, Chapman MJ, Krauss RM, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J 2020;41:2313-30.
4. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 2020;41111-88.
5. Cholesterol Treatment Trialists’ Collaboration. Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials. Lancet 2019;393: 407–15.
6. Ramos R, Comas-Cufí M, Martí-Lluch R, et al. Statins for primary prevention of cardiovascular events and mortality in old and very old adults with and without type 2 diabetes: retrospective cohort study. BMJ 2018;362:k3359.
7. Ponce OJ, Larrea-Mantilla L, Hemmingsen B, et al. Lipid-lowering agents in older individuals: a systematic review and meta-analysis of randomized clinical trials. J Clin Endocrinol Metab 2019;104:1585-94.
8. Bach RG, Cannon CP, Giugliano RP, et al. Effect of simvastatin-ezetimibe compared with simvastatin monotherapy after acute coronary syndrome among patients 75 years or older: a secondary analysis of a randomized clinical trial. JAMA Cardiol 2019;4:846-54.
9. Ouchi Y, Sasaki J, Arai H, et al. Ezetimibe Lipid-Lowering Trial on Prevention of Atherosclerotic Cardiovascular Disease in 75 or Older (EWTOPIA 75): a randomized, controlled trial. Circulation 2019;140: 992-1003.
10. Sinnaeve PR, Schwartz GG, Wojdyla DM, et al. Effect of alirocumab on cardiovascular outcomes after acute coronary syndromes according to age: an ODYSSEY OUTCOMES trial analysis. Eur Heart J 2020;41: 2248-58.
11. Amarenco P, Kim JS, Labreuche J, et al. A comparison of two LDL cholesterol targets after ischemic stroke. N Engl J Med 2020;382(1): 9.
12. Sever P, Gouni-Berthold I, Keech A, et al. LDL-cholesterol lowering with evolocumab, and outcomes according to age and sex in patients in the FOURIER Trial. Eur J Prev Cardiol 2020:2047487320902750.
13. Gencer B, Marston NA, Im KA et al. Efficacy and safety of lowering low-density lipoprotein cholesterol in elderly subjects: a systematic review and meta-analysis of randomized controlled trials. Lancet 2020; DOI:https://doi.org/10.1016/S0140-6736(20)32332-1
14. Nanna MG, Navar AM, Wang TY, et al. Statin use and adverse effects among adults >75 years of age: insights from the Patient and Provider Assessment of Lipid Management (PALM) Registry. J Am Heart Assoc 2018;7(10):e008546.
15. Mortensen MB, Nordestgaard BG. Elevated LDL cholesterol and increased risk of myocardial infarction and atherosclerotic cardiovascular disease in individuals aged 70–100 years: a contemporary primary prevention cohort. Lancet 2020; DOI:https://doi.org/10.1016/S0140-6736(20)32233-9