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Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials
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These 3 pics From a separate CME event
Lancet 2019 Feb 2
Summary
Background
Statin therapy has been shown to reduce major vascular events and vascular mortality in a wide range of individuals, but there is uncertainty about its efficacy and safety among older people. We undertook a meta-analysis of data from all large statin trials to compare the effects of statin therapy at different ages.
Methods
In this meta-analysis, randomised trials of statin therapy were eligible if they aimed to recruit at least 1000 participants with a scheduled treatment duration of at least 2 years. We analysed individual participant data from 22 trials (n=134 537) and detailed summary data from one trial (n=12 705) of statin therapy versus control, plus individual participant data from five trials of more intensive versus less intensive statin therapy (n=39 612). We subdivided participants into six age groups (55 years or younger, 56-60 years, 61-65 years, 66-70 years, 71-75 years, and older than 75 years). We estimated effects on major vascular events (ie, major coronary events, strokes, and coronary revascularisations), cause-specific mortality, and cancer incidence as the rate ratio (RR) per 1⋅0 mmol/L reduction in LDL cholesterol. We compared proportional risk reductions in different age subgroups by use of standard χ2 tests for heterogeneity when there were two groups, or trend when there were more than two groups.
Findings
14 483 (8%) of 186 854 participants in the 28 trials were older than 75 years at randomisation, and the median follow-up duration was 4⋅9 years. Overall, statin therapy or a more intensive statin regimen produced a 21% (RR 0⋅79, 95% CI 0⋅77-0⋅81) proportional reduction in major vascular events per 1⋅0 mmol/L reduction in LDL cholesterol. We observed a significant reduction in major vascular events in all age groups. Although proportional reductions in major vascular events diminished slightly with age, this trend was not statistically significant (ptrend=0⋅06). Overall, statin or more intensive therapy yielded a 24% (RR 0⋅76, 95% CI 0⋅73-0⋅79) proportional reduction in major coronary events per 1⋅0 mmol/L reduction in LDL cholesterol, and with increasing age, we observed a trend towards smaller proportional risk reductions in major coronary events (ptrend=0⋅009). We observed a 25% (RR 0⋅75, 95% CI 0⋅73-0⋅78) proportional reduction in the risk of coronary revascularisation procedures with statin therapy or a more intensive statin regimen per 1⋅0 mmol/L lower LDL cholesterol, which did not differ significantly across age groups (ptrend=0⋅6). Similarly, the proportional reductions in stroke of any type (RR 0⋅84, 95% CI 0⋅80-0⋅89) did not differ significantly across age groups (ptrend=0⋅7). After exclusion of four trials which enrolled only patients with heart failure or undergoing renal dialysis (among whom statin therapy has not been shown to be effective), the trend to smaller proportional risk reductions with increasing age persisted for major coronary events (ptrend=0⋅01), and remained non-significant for major vascular events (ptrend=0⋅3). The proportional reduction in major vascular events was similar, irrespective of age, among patients with pre-existing vascular disease (ptrend=0⋅2), but appeared smaller among older than among younger individuals not known to have vascular disease (ptrend=0⋅05). We found a 12% (RR 0⋅88, 95% CI 0⋅85-0⋅91) proportional reduction in vascular mortality per 1⋅0 mmol/L reduction in LDL cholesterol, with a trend towards smaller proportional reductions with older age (ptrend=0⋅004), but this trend did not persist after exclusion of the heart failure or dialysis trials (ptrend=0⋅2). Statin therapy had no effect at any age on non-vascular mortality, cancer death, or cancer incidence.
Interpretation
Statin 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.
Funding
Australian National Health and Medical Research Council, National Institute for Health Research Oxford Biomedical Research Centre, UK Medical Research Council, and British Heart Foundation.
Discussion
Individual randomised trials of statin therapy have previously reported significant cardiovascular risk reductions among participants older than 65 years but younger than 70 years at the time of randomisation (who were therefore aged >70-75 years at the end of a median of 5 years of scheduled treatment).
Meta-analyses among older people have consistently reported evidence for beneficial effects in secondary prevention, but the evidence has been less clear for primary prevention.
Availability of individual participant data in the CTT Collaboration database has permitted more detailed assessment of the effects of statin therapy at different ages.
In our meta-analysis of data from 28 trials among 186 854 people (with 14 483 [8%] older than 75 years at randomisation), we found slightly smaller proportional risk reductions in major vascular events (ptrend=0⋅06) and vascular deaths (ptrend=0⋅004) with increasing age. The exclusion criteria for 24 trials incorporated at least one of the following: a history of heart failure, poor ejection fraction, poor prognosis (other than from atherosclerotic disease), or the requirement for renal dialysis. However, two trials exclusively enrolled patients with moderate to severe (New York Heart Association Class II-IV) heart failure
and two exclusively enrolled patients with end-stage renal disease requiring dialysis and consequently is not recommended for such patients in the absence of other indications.
Therefore, we did exploratory analyses that excluded these four trials to assess their contribution to the observed trends towards smaller relative reductions with increasing age. Among people without heart or renal failure, we found little evidence of any diminution of benefit with increasing age on major vascular events (ptrend=0⋅3) or on vascular death (ptrend=0⋅2).
Proportional reductions in major vascular events were similar irrespective of age among patients with a history of vascular disease (ie, secondary prevention), but we observed a trend towards smaller proportional risk reductions in those with no known vascular disease (ie, primary prevention), with no independently significant reductions in either of the two age groups including patients older than 70 years. Among patients older than 70 years, only around a fifth of the major vascular events occurred in those with no history of vascular disease, and this relative paucity of evidence has led to further primary prevention trials among older individuals. For example, the STAREE trial aims to assess the effects of atorvastatin 40 mg daily in 18 000 primary prevention patients aged 70 years or older at the time of recruitment.
We observed a trend towards smaller proportional reductions in major coronary events (ptrend=0⋅009) with increasing age, although a significant reduction remained among patients older than 75 years at randomisation. The reasons underlying this trend are unclear. Age-related factors-such as altered pharmacokinetics and pharmacodynamics and an increased risk of drug interactions in the setting of polypharmacy
-would be expected to influence absolute LDL cholesterol reductions from therapy, but these did not differ materially by age. This trend might reflect a reduced capacity for statins to impact on advanced atherosclerotic plaques, greater diagnostic uncertainty at older ages (eg, difficulty separating myocardial infarctions due to unstable atherosclerosis from supply-demand imbalances that occur with other illnesses), and poorer long-term adherence to the assigned study treatment among older people (since our weighted analyses are based on 1 year cholesterol differences). We observed no trends towards smaller proportional reductions in coronary revascularisation procedures or strokes with increasing age, but too few such events occurred among patients older than 75 for us to assess the effects on these outcomes directly. Statin therapy definitely decreases the overall risk of ischaemic stroke and any stroke, but might increase the risk of haemorrhagic stroke.
Individual participant data were not available from one eligible trial in which a large number of strokes (especially haemorrhagic) occurred, and we cannot reliably comment on the relevance of age to the effects of statin therapy on stroke subtypes.
There is a paucity of information on the effects of statins on mortality in people at low risk of vascular disease, and very large trials (eg, the ongoing STAREE trial) would be needed to provide direct evidence of a mortality reduction among older people in primary prevention. However, our overall analyses in a combined primary and secondary prevention population indicate that the proportional reductions in vascular mortality are similar irrespective of age. We have previously shown that statin therapy does not increase the incidence of cancer (as had been suggested) or of non-vascular causes of death.
Consequently, given the similar proportional reductions in vascular mortality in both primary and secondary prevention settings, and the complete absence of effect of statin therapy on non-vascular mortality, reductions in total mortality would be expected in both clinical settings.
Statins have been estimated to increase the risk of myopathy (defined as muscle pain or weakness combined with large increases in blood concentrations of creatine kinase) typically by one case per 10 000 patients treated with statins per year, but this risk can be increased by drug interactions and major comorbidities that are more common in older people.
A meta-analysis of published data for participants older than 65 years at randomisation in statin trials reported no increased risk of less severe muscle-related adverse events. The CTT Collaboration is undertaking a prespecified analysis of reported adverse events in statin trials from original trial records, including examining whether age directly influences the small increase in risk of diabetes, and whether statins adversely influence cognition (noting that no excess risks have been identified in any large randomised trials).
The selection criteria used among the 28 trials contributing to this meta-analysis, and differences in when they were conducted, mean that the absolute risk of major vascular events and mortality in our overall study population is not likely to be representative of any contemporary population. Therefore, we have not produced estimates of the absolute effects of statin therapy directly from the numbers of events observed in these trials. By contrast, the proportional effects observed in this meta-analysis are likely to be widely generalisable. Consequently, as the proportional reductions in major vascular events appeared to diminish only slightly (if at all) with increasing age, while untreated absolute risks of major vascular events in the general population increase exponentially with age, the absolute benefits of a given absolute reduction in LDL cholesterol with statin therapy would be expected to be substantially greater among older individuals. For example, in the primary prevention setting, two individuals aged 63 years and 78 years with otherwise identical risk factors might have projected major vascular event rates of 2⋅5% versus 4⋅0% per year, respectively. Reducing those risks by a fifth with a 1⋅0 mmol/L LDL cholesterol reduction would prevent first major vascular events from occurring each year in 50 individuals aged 63 years and 80 individuals aged 78 years per 10 000 people treated.
In conclusion, statin therapy produces significant reductions in major vascular events, irrespective of age. There is less definitive direct evidence of benefit in the primary prevention setting among patients older than 75 years, but evidence supports the use of statin therapy in older people considered to have a sufficiently high risk of occlusive vascular events.
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