Statins reduce vascular events in all age groups, including people older than 75 years, according to the results of a new meta-analysis from the Cholesterol Treatment Trialists' Collaboration.

"There are robust data on the benefits of statins in preventing premature cardiovascular mortality and morbidity in people aged under 75, but the perception of benefit in the elderly has been unclear as individual trials have not included large numbers in this age group, and consequently, there is underuse of statins in the over 75s," coauthor of the new meta-analysis, Colin Baigent, FRCP, Clinical Trial Service Unit, Nuffield Department of Population Health, Oxford, UK, told Medscape Medical News.

"By combining data from all relevant trials, our data show a clear benefit in this older age group," Baigent said. "There is a very slight diminution of the relative benefit of statins on vascular events in the elderly compared with younger age groups but the absolute benefits are often greater in the elderly as the risk of vascular death is greater in the older age group."

The meta-analysis, which summarizes evidence from 28 randomized controlled trials including 186,854 patients, 14,483 (8%) of whom were over aged 75 years, was published online February 2 in The Lancet.

Baigent believes that society is not focused enough on preventative medical care in the elderly. "We can be somewhat ageist in our approach," he said. "Our attitude seems to be that their time has been — that it is not worth treating them with preventative medication. But every old person's greatest fear is having a stroke and being disabled and dependent. This is unhealthy aging. Statins can reduce that risk."

In addition to stroke, reducing the incidence of myocardial infarction will also reduce heart failure, further contributing to healthy aging, he said. "These drugs are cheap and safe, and our data show they should be used much more widely in the elderly population."

He estimates that statins are currently being taken by about one third of the over 75s in the UK. "We could save several thousand premature deaths and vascular events in the UK alone by increasing the number of elderly on statins," he says.

For the meta-analysis, the researchers analyzed individual participant data from 22 trials and detailed summary data from one trial of statin therapy versus control, plus individual participant data from five trials of more intensive versus less intensive statin therapy, with a median follow-up in all trials of 4.9 years.

Participants were divided 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). Effects of statins on major vascular events, cause-specific mortality, and cancer incidence were estimated and compared in the different age groups.

Results showed that, overall, statin therapy or a more intensive statin regimen produced a 21% proportional reduction in major vascular events per 1.0 mmol/L reduction in LDL cholesterol (rate ratio [RR], 0.79).

Significant reductions in major vascular events were seen in all age groups, and although proportional reductions in major vascular events diminished slightly with age, this trend was not significant (P trend = .06).

Overall, statin or more intensive therapy yielded a 24% proportional reduction in major coronary events per 1.0 mmol/L reduction in LDL cholesterol (RR, 0.76), and there was a trend towards smaller proportional risk reductions with increasing age (P trend = .009).

Statin use or a more intensive statin regimen was also linked to a 25% proportional reduction in the risk of coronary revascularization procedures with statin therapy per 1.0 mmol/L lower LDL cholesterol (RR, 0.75), which did not differ significantly across age groups (P trend = .6).

Similarly, the proportional reductions in stroke of any type (RR, 0.84) did not differ significantly across age groups (P trend = .7).

After exclusion of four trials that 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 (P trend = .01) and remained nonsignificant for major vascular events (P trend = .3).

The proportional reduction in major vascular events was similar, irrespective of age, among patients with pre-existing vascular disease (P trend = .2), but appeared smaller among older than younger individuals not known to have vascular disease (P trend = .05).

There was a 12% proportional reduction in vascular mortality per 1.0 mmol/L reduction in LDL cholesterol (RR, 0.88), with a trend towards smaller proportional reductions with older age (P trend = .004), but this trend did not persist after exclusion of the heart failure or dialysis trials (P trend = .2).

Statin therapy had no effect at any age on nonvascular mortality, cancer death, or cancer incidence.

What About Primary Prevention?

In their discussion, the researchers note that previous 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. They say that the availability of individual participant data in this meta-analysis has permitted more detailed assessment of the effects of statin therapy at different ages.

They report that their results show smaller proportional risk reductions in those with no known vascular disease (the primary prevention population) compared with those with established vascular disease (the secondary prevention population). There were no independently significant reductions in patients older than 70 years but there were not enough events in the older age group of the primary prevention population for definitive answers, they note. Further trials in this population are ongoing.

"In our study there was more limited evidence in the primary prevention context, but given the clear evidence overall that the relative benefits were similar irrespective of age and the consistency of the effects at all ages in primary prevention, it is reasonable to infer that statins are likely to be effective for primary prevention in those aged over 75," Baigent told Medscape Medical News.

In The Lancet article, the authors emphasize that even if the proportional reductions in major vascular events brought about by statins diminishes slightly with increasing age, the untreated absolute risks increase exponentially with age, so the absolute benefits of a given reduction in LDL cholesterol with statin therapy would be expected to be substantially greater among older individuals.

They give an example in the primary prevention setting of two individuals aged 63 years and 78 years with otherwise identical risk factors who might have projected major vascular event rates of 2.5% versus 4.0% per year, respectively. Reducing those risks by a fifth by reducing LDL cholesterol by 1.0 mmol/L would prevent a first major vascular event from occurring each year in 50 individuals aged 63 years and 80 individuals aged 78 years per 10,000 people treated, they report.

"Obviously, there are some people for whom these drugs will be inappropriate — those on other medications which cause interactions or if they have a very limited lifespan due to cancer or another terminal condition," Baigent added. "We also know statins don't benefit patients with heart failure — probably because these patients mainly die of pump failure or sudden arrhythmic death, which statins do not influence. But for many of the others in the older population, it appears they will benefit as much as — if not more than — younger patients."

'Misinformation' About Adverse Effects?

On the issue of the adverse effects of statins, Baigent believes there has been a lot of misinformation.

"Much of this confusion arises from potentially biased observational studies, which are not able to provide reliable information," he said. "The perception that statins cause troublesome problems like muscle pain is just that — a perception. Muscle pain is very common and the randomized trial evidence has demonstrated very clearly that the vast majority of muscle symptoms that occur in people taking a statin are not caused by the drug."


He adds: "The randomized trial evidence, which is unbiased and should be the sole source of information that we trust to guide practice, indicates that statins do cause myopathy (rarely rhabdomyolysis), a slightly increased risk of diabetes, and hemorrhagic stroke. The excess risk of all known adverse effects is very small (for example, the incidence of myopathy is about 1 in 10,000 per year) and far exceeded by the benefits of statin therapy.

"Although the absolute risks of these adverse effects are higher in the elderly, so too are the absolute risks of vascular disease, so the overall balance of benefit and risk is still heavily weighted towards benefit in those aged over 75," Baigent concludes.

In an accompanying editorial, Bernard M.Y. Cheung, MB BChir, PhD, and Karen S.L. Lam, MD, Queen Mary Hospital, University of Hong Kong, point out some limitations of the new meta-analysis.

These include that the patients in trials are "highly selected, with fewer comorbidities, less drug intolerance, and better adherence than the general patient population," and "the included clinical trials concentrated on efficacy endpoints — adverse events, especially if nonserious, were not as fully recorded and analyzed, which limited the ability of this meta-analysis to develop insights into the risks of side effects for older people with statins."

The editorialists say that more research in older people is needed to enrich the evidence on the risks and benefits of statins.

They say the benefits of statins in the prevention of major vascular events have been shown to be much greater than their risks, and the present meta-analysis, which includes people older than standard trial populations, echoes this conclusion. But they add that when statins are used in people with low cardiovascular risk, the risks and benefits need to be weighed against each other.

"The challenge for the healthcare profession and the media is to convey risks and benefits in ways that patients can understand, enabling them to make an informed choice," they note.

The meta-analysis was supported by Australian National Health and Medical Research Council, National Institute for Health Research Oxford Biomedical Research Centre, UK Medical Research Council, and British Heart Foundation. Disclosures for the authors are listed with the article.

Lancet. Published online February 2, 2019. Abstract, Editorial

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