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Primary prevention with statins for older adults - Editorial / Statins for primary prevention of cardiovascular events and mortality in old and very old adults with and without type 2 diabetes: retrospective cohort study
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Download the PDF here
Download the PDF here
BMJ 2018
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 (Published 05 September 2018)
Patient preference remains the guiding principle while we wait for better evidence
The overall prevalence, incidence, and mortality from cardiovascular disease (CVD) has decreased over the past 10 years in the developed world.1 But primary prevention remains important, particularly for adults aged more than 65 years, who experience substantial morbidity after an initial cardiovascular event-up to one third have a further event (stroke, myocardial infarction) or die within three years.2
Over the past decade, statin prescriptions for primary prevention of CVD-usually either simvastatin or atorvastatin-have increased for those aged between 60 and 80 years.3 A recent change in UK guidance means that all men aged more than 60 and women aged more than 75 are now eligible for statin treatment.4 Are statins beneficial for primary prevention of CVD in adults aged 75 or older and what are the risks?
The evidence
In a linked large retrospective cohort study of patients aged 75 or more, Ramos and colleagues (doi:10.1136/bmj.k3359) found no reduction in CVD (a composite of coronary heart disease and stroke) in those without diabetes using statin treatment for primary prevention.5 However, there was a lower risk of CVD in those aged 75 or more with diabetes, at least up to age 85, after which the effects of statins on primary prevention of CVD attenuated.
The authors did not find an increased risk of myopathy, liver toxicity, or type 2 diabetes mellitus associated with statin use in older adults. Previous research had suggested an increased risk of myopathy in this age group compared with younger adults; however, these participants were taking high intensity statins,6 which in Ramos and colleagues' cohort were the minority (<20%).
Concerns about statins and cognition have previously been expressed7 but were not recorded in this study. Current evidence from trial data does not support a link between statins and cognitive dysfunction.7 However, concerns remain about the vulnerability of this age group to adverse effects from polypharmacy and the general lack of evidence to guide the prevention of CVD.8 A recent review of primary prevention studies of randomised controlled trials found no evidence of a reduction in CVD mortality in those older than 75, and it concluded that follow-up was too limited to exclude important adverse events from lipid lowering drugs.9 Evidence, however, supports a reduction in a composite outcome of myocardial infarction, stroke, and revascularisation. The exact number needed to treat to prevent one CVD event in this age group remains unclear as only one randomised trial reported the percentage of participants aged more than 75.10
In the study by Ramos and colleagues, any protective effect of statins was limited to participants with type 2 diabetes aged between 75 and 84, with no effect in those without diabetes. These observational findings are exploratory however and should be tested further in randomised trials-to rule out any confounding and to study the effect of statins on CVD death, which were not recorded in the database used for this study.
The guidelines
Current guidance on lipid management in older adults is inconsistent: the National Institute for Health and Care Excellence recommends statins for primary prevention up to age 84, the European Society of Cardiology recommends treatment to age 65, and the American Heart Association up to age 75.111213 Both the American Heart Association and NICE recognise that trial evidence for those aged more than 75 is limited, yet NICE continues to recommend statins up to the age of 84 consistent with the upper age limit of the QRISK2 CVD risk calculator.1112 For those with type 2 diabetes, NICE recommends statin prescription guided by a CVD risk calculation, whereas the American Heart Association recommends statins without risk calculation.1112
Since age alone for those aged more than 75 is enough to cross the CVD risk threshold for primary prevention, the biggest challenge for clinicians is how to stratify risk among those aged more than 75 to inform shared decision making.8
The ongoing STAREE (Statins for Reducing Events in the Elderly) trial is an Australian trial of primary prevention based in general practice comparing atorvastatin 40 mg with placebo in adults aged more than 70.14 The investigators hope to recruit 18 000 participants and aim to report findings in 2022. The primary outcome is time to death, or incident dementia, or time to a fatal or non-fatal cardiovascular event.11 The challenge for investigators will be whether they can run the trial long enough to evaluate slowly progressive conditions such as cognitive impairment.
Decision time
Observational data have shown that researchers and patients having differing views on the relative importance of morbidity and mortality.15 Patients aged 65 or older prioritised reductions in myocardial infarction and stroke over avoiding death, in contrast with researchers and those younger than 65. Therefore, if in the process of shared decision making, older patients express a preference for extending longevity, then current evidence supporting statins for primary prevention remains limited. A patient preference for reduction in myocardial infarction or stroke, however, might help to tilt the balance in favour of statin prescription, but the absolute risk reduction and number needed to treat to prevent a CVD event in older patients remains uncertain.9
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Statins for primary prevention of cardiovascular events and mortality in old and very old adults with and without type 2 diabetes: retrospective cohort study
What is already known on this topic
• The efficiency of statins in reducing any cardiovascular event and also cardiovascular mortality in secondary prevention in those aged 75 years or older is well established
• Statin prescriptions to elderly patients have increased in recent decades
• Evidence on the effects of statins in primary prevention in those older than 74 years and particularly in those aged 85 years or older is lacking
What this study adds
• Statins were not associated with a reduction in atherosclerotic cardiovascular disease (CVD) or all cause mortality in primary prevention in people without diabetes older than 74 years independently of age subgroup
• Statins were significantly related to a reduction in incidence of atherosclerotic CVD and in all cause mortality in people with type 2 diabetes mellitus; this effect was substantially reduced after the age of 85 and disappeared in nonagenarians
• These results do not support the widespread use of statins in old and very old populations, but they do support treatment in those with diabetes who are younger than 85 years
Abstract
Objective To assess whether statin treatment is associated with a reduction in atherosclerotic cardiovascular disease (CVD) and mortality in old and very old adults with and without diabetes.
Design Retrospective cohort study.
Setting Database of the Catalan primary care system (SIDIAP), Spain, 2006-15.
Participants 46 864 people aged 75 years or more without clinically recognised atherosclerotic CVD. Participants were stratified by presence of type 2 diabetes mellitus and as statin non-users or new users.
Main outcome measures Incidences of atherosclerotic CVD and all cause mortality compared using Cox proportional hazards modelling, adjusted by the propensity score of statin treatment. The relation of age with the effect of statins was assessed using both a categorical approach, stratifying the analysis by old (75-84 years) and very old (≥85 years) age groups, and a continuous analysis, using an additive Cox proportional hazard model.
Results The cohort included 46 864 participants (mean age 77 years; 63% women; median follow-up 5.6 years). In participants without diabetes, the hazard ratios for statin use in 75-84 year olds were 0.94 (95% confidence interval 0.86 to 1.04) for atherosclerotic CVD and 0.98 (0.91 to 1.05) for all cause mortality, and in those aged 85 and older were 0.93 (0.82 to 1.06) and 0.97 (0.90 to 1.05), respectively. In participants with diabetes, the hazard ratio of statin use in 75-84 year olds was 0.76 (0.65 to 0.89) for atherosclerotic CVD and 0.84 (0.75 to 0.94) for all cause mortality, and in those aged 85 and older were 0.82 (0.53 to 1.26) and 1.05 (0.86 to 1.28), respectively. Similarly, effect analysis of age in a continuous scale, using splines, corroborated the lack of beneficial statins effect for atherosclerotic CVD and all cause mortality in participants without diabetes older than 74 years. In participants with diabetes, statins showed a protective effect against atherosclerotic CVD and all cause mortality; this effect was substantially reduced beyond the age of 85 years and disappeared in nonagenarians.
Conclusions In participants older than 74 years without type 2 diabetes, statin treatment was not associated with a reduction in atherosclerotic CVD or in all cause mortality, even when the incidence of atherosclerotic CVD was statistically significantly higher than the risk thresholds proposed for statin use. In the presence of diabetes, statin use was statistically significantly associated with reductions in the incidence of atherosclerotic CVD and in all cause mortality. This effect decreased after age 85 years and disappeared in nonagenarians.
Introduction
Cardiovascular disease (CVD) is the leading cause of death globally.1 Older populations are especially vulnerable to CVD, with incidence and mortality rates almost three times higher in those older than 74 years than in younger people.2 In addition, projections of population growth anticipate that people older than 74 years will represent more than 10% of the population in developed countries in 2050.3 Consequently, prevention of CVD in this population will be a major worldwide health policy challenge during the next decades.
Evidence from randomised clinical trials and meta-analysis supports statin treatment for the secondary prevention of CVD in those aged 75 years and older.4567 Data from meta-analyses also support statins for the primary prevention of CVD in those aged 65 years or more.89 This evidence does not, however, include people older than 74 years, and especially those older than 84 years-an age group that is underrepresented in clinical trials and observational studies.10 People aged 85 years and older represent a rapidly increasing portion of the population worldwide and many experience disease and disability, with heavy costs in health and social care.11 Recent reports from post hoc secondary analyses of data from the Lipid-Lowering Trial component of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT) showed no benefit of pravastatin in primary prevention in adults aged 75 years and older.12
This concern also applies to older patients with type 2 diabetes mellitus-a particularly high risk group in primary prevention of CVD. Those with longstanding diabetes have a risk of coronary heart disease similar to that of patients with a history of coronary heart disease.13 Still, the benefit of statins in primary prevention in older people with diabetes has not been sufficiently evaluated.14 Notwithstanding this uncertainty, the number of prescriptions for statins in those aged 75 years or older have increased in recent decades.1516 Moreover, current recommendations of the most implemented guidelines on cardiovascular prevention classify almost all patients aged 75 years or older as eligible for statin treatment based on 10 year risk estimation, because CVD incidence (ie, risk) is highly dependent on age.17181920
The older population might also be more susceptible to adverse effects and drug interactions owing to comorbidities and polypharmacy, although these aspects have been poorly studied.21 In this scenario, decisions on statin use in people older than 74 years are made individually and are not supported by high quality evidence; further research is needed.17 We assessed whether the use of statins was associated with a reduced incidence of atherosclerotic CVD and mortality in older people initially free of CVD, by type 2 diabetes and age.
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