Large reduction of major vascular events with statins in older individuals
Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trialsLiterature - Cholesterol Treatment Trialists’ Collaboration - The Lancet 2019;393;407-15
Introduction and methods
Reduction in low-density lipoprotein cholesterol (LDL-c) levels with statins decreases the risk of major vascular events and vascular mortality, with similar proportional risk reductions for gender types  and absolute risk categories . However, rates of statin use have shown to be substantially lower in people >75 years, especially in those with no evidence of occlusive vascular disease, showing differences in both prescribing and compliance [3,4]. This might be due to uncertainty about statin efficacy and safety in an older population, since only a relatively small number of individuals aged >75 years were included in randomized trials, and many older subjects have non-CV comorbidities [6-10].
This meta-analysis including individual participant data (n=14.483) from 28 large randomized controlled trials on statin treatment in the Cholesterol Treatment Trialists’ (CTT) Collaboration therefore assessed the effects of statin treatment at different ages and explored the effects of statins among individuals aged >75 years. Randomized trials were eligible for inclusion if the main effect of at least one of the trial interventions was to lower LDL cholesterol, the trial was unconfounded with respect to this intervention (i.e., no other differences in modification of risk factors between the relevant treatment groups were intended), and the trial aimed to recruit 1000 or more participants with a scheduled treatment duration of at least 2 years.
The effect of statins was measured per 1.0 mmol/L reduction in LDL-c in all trials. Effects of statin treatment were compared between 6 age groups: ≤55, 56-60, 61-65, 66-70, 71-75, >75 years. Older patients were underrepresented in 4 trials that enrolled exclusively patients with heart failure (HF) or receiving dialysis, who do not benefit from statin therapy. The effects of statin treatment were therefore also examined after exclusion of these 4 trials. Median follow-up was 4.9 years.
Prespecified outcomes were major coronary events (defined as non-fatal myocardial infarction or coronary death), coronary revascularization (angioplasty or bypass grafting), stroke (subdivided by type), site-specific cancers, and cause-specific mortality. Major vascular events were defined as the composite of major coronary events, coronary revascularization, and stroke.
- This meta-analysis included 22 trials (n=134.537) with individual participant data and 1 trial with summary data (n=12.705) on statin use vs. control therapy, and 5 trials (n=39.612) on more intensive vs. less intensive statin treatment.
- Statin treatment or a more intensive statin regimen resulted in a 21% reduction of proportional risk in first major vascular event (RR: 0.79, 95%CI: 0.77-0.81) in all age groups including those aged >75 years (RR: 0.87, 95%CI: 0.77-0.99), compared with control or a less intensive statin therapy. Although reductions in major vascular events decreased slightly with increasing age, this trend was not significant (P=0.06), and this trend was even more diminished after exclusion of the 4 HF and dialysis trials (P=0.3).
- Statin treatment or more intensive statin regimen resulted in a 24% (RR: 0.76, 95%CI: 0.73-0.79) proportional reduction in major coronary events, compared with control or less intensive statin therapy. This proportional reduction was significantly smaller with increasing age (P-trend=0.009), which remained significant after exclusion of HF and dialysis trials. Nevertheless, a significant reduction in major coronary events was observed in those >75 years (RR: 0.82, 95%CI: 0.70-0.96), which was not significantly different from patients ≤75 years.
- A 25% (RR: 0.75, 95%CI: 0.73-0.78) proportional reduction in the risk of coronary revascularization procedures was seen with statin treatment or a more intensive statin regimen irrespective of age (P-trend=0.6), compared with control or less intensive statin therapy. However, no apparent effect was observed among patients >75 years (RR: 1.02, 95%CI: 0.75-1.40).
- The effect of statin treatment or a more intensive statin regimen on any stroke (RR: 0.84, 95%CI: 0.80-0.89) did not significantly differ between age groups (P-trend=0.7).
- Among patients with known vascular disease at study enrollment, similar proportional reductions in major vascular events (RR: 0.75, 95%CI: 0.71-0.80) were observed across age groups, regardless of HF and dialysis trials were included or excluded (P-trend=0.2 and P=0.9, respectively). Among patients with no history of vascular disease smaller proportional risk reductions (RR: 0.80, 95%CI: 0.77-0.82) were seen with increasing age (P-trend=0.05), which remained after exclusion of patients with HF or dialysis (P-trend=0.03).
- Vascular mortality was proportionally reduced by 12% (RR: 95%CI: 0.85-0.91), with smaller proportional reductions with increasing age (P-trend=0.004). However, after exclusion of HF or dialysis trials, the apparent trend disappeared (P-trend=0.2).
- Overall or by age, no effect was found of statin therapy on all non-vascular mortality (RR: 0.96, 95%CI: 0.92-1.01), nor on death due to cancer or incident cancer cases.
- A significant reduction in all-cause mortality (RR 0.91, 95% CI:0.88–0.93) was observed, with a trend towards smaller proportional risk reduction with increasing age (P=0.04), that disappeared after exclusion of HF or dialysis trials (P=0.1).
Statin use resulted in significant reductions in major vascular events, regardless of age. Although there is less definitive evidence of beneficial effects in the primary prevention setting among patients >75 years, these data support the use of statin therapy in older patients with a sufficiently high risk of occlusive vascular events.
Although a statin is the main ingredient in polypills for CVD prevention, there are still questions left to be answered on statin use. Cheung and Lam  explain that evidence for statin use in primary prevention in older populations of patients is still lacking and that the message that statins should be considered to lower CV risk in those at risk, even if they are older, needs to be reinforced.
The present meta-analysis showed reduced major vascular events in individuals at risk, even when they were older, suggesting that statins should be considered in CV prevention in people at risk. However, the authors note some limitations of the meta-analysis conducted by the Cholesterol Treatment Trialists’ Collaboration: the high selection of patients with fewer comorbidities, less drug intolerance, and better adherence than the general patient population, the mean age of the trial participants of 63 years and the small number of patients who were older than 75 years (8%), the focus on efficacy outcomes and therefore the limited ability to develop insights into the risks of side-effects for older people with statins, and both the exclusion of trials that were not part of the collaboration and inclusion of old trials that do not reflect contemporary management. These limitations indicate that ‘more research in older people is needed to enrich the evidence on the risks and benefits of statins’.
When considering to prescribe statins in people with low CV risk, the risks and benefits of statins need to be weighed against each other, according to the authors. Statins have been associated with a slight increase in incidence of muscle plain, diabetes, and hemorrhagic stroke, however, their beneficial effects on reducing major vascular events are shown to be much greater. They conclude: ‘The present meta-analysis that includes people older than standard trial populations echoes this conclusion. 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’.