Never too old for statin treatment?
Authors: Bernard M Y Cheung, Karen S L Lam
Journal: The Lancet (2019)

In 2005, in a participant-level meta-analysis of large randomised controlled trials, the Cholesterol Treatment Trialists' (CTT) Collaboration conclusively showed that for most patients HMG-CoA reductase inhibitors (statins) reduced major adverse cardiovascular events.1Baigent C Keech A Kearney PM et al.Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins.Lancet. 2005; 366: 1267-1278Summary Full Text Full Text PDF PubMed Scopus (5760) Google Scholar Since then, generic versions of commonly used statins have become available. An evidence-based life-saving class of drugs with minimal known side-effects is therefore available, and are largely affordable even in lower income countries and for national health services. A statin is a key ingredient in polypills for cardiovascular disease prevention. So why is there a need for another meta-analysis? The first reason is a scientific one. There is a gap in the evidence for statins for primary prevention in people older than 75 years.2Gurwitz JH Go AS Fortmann SP Statins for primary prevention in older adults: uncertainty and the need for more evidence.JAMA. 2016; 316: 1971-1972Crossref PubMed Scopus (58) Google Scholar In the PROSPER trial of 5084 male and female elderly patients in Scotland, Ireland, and the Netherlands, the primary endpoint, a composite of coronary death, non-fatal myocardial infarction, and fatal and non-fatal stroke, was significantly reduced in the secondary but not in the primary prevention subgroup.3Shepherd J Blauw GJ Murphy MB et al.Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial.Lancet. 2002; 360: 1623-1630Summary Full Text Full Text PDF PubMed Scopus (2984) Google Scholar In the HOPE-3 trial, which randomised 12 705 men and women with intermediate risk of cardiovascular disease from 21 countries to 10 mg rosuvastatin or placebo, statin therapy did not reduce risk in participants aged 70 years or older.4Ridker PM Lonn E Paynter NP Glynn R Yusuf S Primary prevention with statin therapy in the elderly: new meta-analyses from the contemporary JUPITER and HOPE-3 randomised trials.Circulation. 2017; 135: 1979-1981Crossref PubMed Scopus (78) Google Scholar An ongoing trial (STAREE; NCT02099123) is investigating the benefits and risks of primary prevention in healthy participants aged 70 years and above in Australia. Initiation of statin therapy in older patients requires special considerations, including pharmacokinetics, drug–drug interactions, life expectancy, quality of life, frailty, cognitive function, comorbidities, and patient choice. Lipid lowering might prevent cardiovascular events but cannot reverse established severe atherosclerosis. The second reason to update the CTT meta-analysis is to reinforce the message that statins should be considered for cardiovascular prevention in people at risk, even if they are older in age. Ongoing medical debate exists about whether the risks of statins have been under-recognised5Godlee F Adverse effects of statins.BMJ. 2014; 348: g3306Crossref PubMed Scopus (41) Google Scholar or exaggerated.6Collins R Reith C Emberson J et al.Interpretation of the evidence for the efficacy and safety of statin therapy.Lancet. 2016; 388: 2532-2561Summary Full Text Full Text PDF PubMed Scopus (1136) Google Scholar In The Lancet, the latest meta-analysis by the CTT Collaboration7Cholesterol Treatment Trialists' CollaborationEfficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials.Lancet. 2019; 393: 407-415Summary Full Text Full Text PDF PubMed Scopus (395) Google Scholar focuses on the influence of advancing age on major endpoints in 28 statin trials. Overall, statin therapy or a more intensive statin regimen produced a 21% (rate ratio [RR] 0·79, 95% CI 0·77–0·81) proportional reduction in major vascular events per mmol/L reduction in LDL cholesterol, but in participants older than 75 years, the relative risk reduction was slightly less (RR 0·87, 0·77–0·99), especially among those without previous vascular disease (0·92, 0·73–1·16). As statins have not been shown to reduce cardiovascular events in patients with cardiac or renal failure, inclusion of older participants with cardiac or renal dysfunction in the trials might be an explanation for this result, which was borne out by additional analyses excluding trials conducted in cardiac and renal failure patients. Statin therapy is often discontinued in older patients for various reasons, such as concomitant diseases and perceptions of risk–benefit.8Ofori-Asenso R Jakhu A Curtis AJ et al.A systematic review and meta-analysis of the factors associated with non-adherence and discontinuation of statins among people aged ≥65 years.J Gerontol A Biol Sci Med Sci. 2018; 73: 798-805Crossref PubMed Scopus (41) Google Scholar As clinical trials are analysed on an intention-to-treat basis, discontinuation or poor adherence can lead to a diminished drug effect. Furthermore, statins are not a treatment for hypertension, hypotension, cardiac arrhythmia, or ventricular dysfunction, all of which can cause heart attack, stroke, and death. Even if the relative risk reduction in people older than 75 years is less than expected, statin therapy might still be justified by a high baseline cardiovascular risk, which is usually present in older people. Among trial participants older than 75 years, the absolute risk reduction in major vascular events was roughly 0·5% per year per mmol/L decrease in LDL cholesterol. This risk reduction would be expected to be higher in high-risk patients. The present meta-analysis7Cholesterol Treatment Trialists' CollaborationEfficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials.Lancet. 2019; 393: 407-415Summary Full Text Full Text PDF PubMed Scopus (395) Google Scholar makes a case to reduce LDL cholesterol in people at risk of cardiovascular events regardless of age, provided that the benefits outweigh the risks and the patient accepts long-term treatment. There are limitations in this meta-analysis.7Cholesterol Treatment Trialists' CollaborationEfficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials.Lancet. 2019; 393: 407-415Summary Full Text Full Text PDF PubMed Scopus (395) Google Scholar First, patients in trials are highly selected, with fewer comorbidities, less drug intolerance, and better adherence than the general patient population. Second, the mean age of the trial participants was 63 years, and only 14 483 (8%) of 147 242 participants were older than 75 years. Third, the included clinical trials concentrated on efficacy endpoints—adverse events, especially if non-serious, were not as fully recorded and analysed, which limited the ability of this meta-analysis to develop insights into the risks of side-effects for older people with statins. Last, not all relevant trials could be included in the meta-analysis if they were not part of the collaboration, and the trials included, if done many years ago, might not reflect contemporary management. More research in older people is needed to enrich the evidence on the risks and benefits of statins. No drug is completely harmless. When statins are used in people with low cardiovascular risk, the risks and benefits need to be weighed against each other. Statins have been associated with a slight increase in incidence of muscle pain, diabetes, and haemorrhagic stroke, but their benefits in prevention of major vascular events are shown to be much greater.6Collins R Reith C Emberson J et al.Interpretation of the evidence for the efficacy and safety of statin therapy.Lancet. 2016; 388: 2532-2561Summary Full Text Full Text PDF PubMed Scopus (1136) Google Scholar The present meta-analysis that includes people older than standard trial populations echoes this conclusion.7Cholesterol Treatment Trialists' CollaborationEfficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials.Lancet. 2019; 393: 407-415Summary Full Text Full Text PDF PubMed Scopus (395) Google Scholar The challenge for the health-care profession and the media is to convey risks and benefits in ways that patients can understand, enabling them to make an informed choice. BMYC reports personal fees from Amgen, Pfizer, and Roche, outside the area of work commented on here. KSLL reports personal fees from MSD and AstraZeneca, outside the area of work commented on here. Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trialsStatin therapy produces significant reductions in major vascular events irrespective of age, but there is less direct evidence of benefit among patients older than 75 years who do not already have evidence of occlusive vascular disease. This limitation is now being addressed by further trials. Full-Text PDF Open Access