Starting Before or After 75 Years
There is robust evidence that statin treatment—when started in midlife—is beneficial for reducing even total mortality in primary prevention [
12••]. It is difficult to comprehend that this effect would vanish after some arbitrary age threshold, and there are several studies where ongoing statin treatment is associated with better prognosis in older people, too [
10,
20,
21]. The ACC/AHA guideline supports continuing statin beyond 75 years in persons already taking and tolerating the drug [
11••], and an algorithm has been published to guide treatment [
10].
It can be claimed that only “deprescribing” studies could confirm the question about benefits of continuing earlier started treatment in old age. Some studies have investigated the effects of discontinuation at the very end of life and showing benefit for quality of life [
22]. However, an unblinded study is open to bias. Given the better prognosis with statin treatment in epidemiological studies, also ethical questions should be considered in discontinuation of statin treatment in old age [
23]. There is an ongoing trial in France, Statins In The Elderly (SITE, NCT02547883), which is recruiting 2430 participants aged 75 years and over and treated in primary prevention. Among them, statin treatment will be randomly discontinued or continued. The participants will be followed-up every 3 months for a total of 36 months, and clinical events and economic impact were also registered. The trial has started in 2016 and expected to close in 2021.
Heterogeneity of Older People
People older than 75 years are biologically very heterogeneous, ranging from institutionalized patients with dementia to robust and strong old individuals. They may have features (frailty, multimorbidity, polypharmacy, increased vulnerability to adverse effects, competing mortality, etc.), which usually have not been addressed or such patients excluded in randomized trials, and this must be taken into account when individual prevention is considered. Prevention may also be futile, if started too late—for example, in patients with dementia, late-stage heart, or kidney failure [
24‐
26]. On the other hand, when used in persons with low risk, adverse effects of drugs may exceed benefits.
Age itself is a powerful risk factor due to the accumulation of cellular damage from aging and risk factor burden. Moreover, the predictive value of traditional risk factors—e.g., cholesterol, blood pressure, and obesity—may be reversed in old age (see previous texts). Therefore, focusing primary prevention to those older individuals with most benefit is challenging. Assessment of frailty [
27], biomarkers—such as homocysteine [
28]—or more conventional indicators of ASCVD, for example, coronary calcium score, carotid intima media thickness, and genetic markers, may offer methods to better assess risk, but their use is not established.
On the other hand, it is reassuring that in epidemiologic studies ongoing statin treatment has been beneficial irrespective of multiprognostic factors [
20,
21] and statin efficacy noted in RCTs is similar in “real-life” and with other drug treatments [
29]. The significance of potential adverse effects of statins is accentuated in primary prevention, because benefits are smaller (or are achieved later) in people at lower ASCVD risk. These will be discussed next.
Role of Adverse Effects
Common concerns of statin treatment in older people have included fears of myalgia and myositis, diabetes, cognitive disorders, hemorrhagic stroke, fatigue, and loss of energy leading to less physical activity, worsened quality of life, and drug interactions in patients with polypharmacy. As most of these have not been observed in RCTs, this has been explained by the focus of clinical trials on efficacy endpoints, and, therefore, less serious adverse effects may not have been fully recorded. They would nevertheless be important in frail older people if they lead, for example, to physical inactivity and functional decline. Frail individuals with comorbidity and polypharmacy may also be more prone to adverse effects and drug interactions, and participants with these problems have been usually excluded from clinical trials. Furthermore, serious adverse events may also be more frequent in “real life” conditions than in controlled studies.
The RCT-established and well-known adverse effects of statins have included effects on liver enzymes, musculoskeletal effects, and development of diabetes [
12••]. Although several other adverse effects have been suspected, there is seldom consistent evidence of a cause–effect relationship [
30,
31].
The muscle-related effects are potentially the most important ones for an older patient. These effects range from pains without serum creatinine kinase (CK) elevations to rhabdomyolysis, but the occurrence of life-threatening toxicity is rare. Milder symptoms, myalgia and cramps, without CK elevations are common in “real-life” settings, but true cause–effect relationship is often difficult to establish. In a large observational study (PRIMO), muscle symptoms were reported by 10.5% [
32], which nevertheless would mean a large number of individuals, because statin use is so common.
Among vulnerable older people, adverse muscle effects could promote sarcopenia and predispose to frailty, falls, and morbidity especially in nursing home residents. However, hard evidence for this is absent in available studies [
10], and statin treatment has no general deteriorating effect on frailty nor on physical function. At the individual level, it is still important to observe potential adverse effects like drug interactions, dehydration, and comorbidity in a frail patient.
Elevations of hepatic transaminases usually resolve spontaneously, after dose reduction or discontinuation of the drug. Progression to serious liver damage is extremely rare, and routine liver enzyme testing is not needed.
Statin treatment is associated with a slightly increased risk of diabetes, but, in older people, the clinical significance is unclear, and statin treatment also benefits patients with diabetes [
12••]. At present, there is no firm evidence that statin treatment would have either positive or negative effect on cognition [
12••,
30,
31], and very low cholesterol is not associated with cognitive impairment [
33]. Given the established effect of preventing ischemic stroke [
12••], a risk factor for cognitive decline, statin treatment could be rather anticipated to be beneficial through that mechanism. Slightly increased risk of hemorrhagic stroke has been noted in patients with prior stroke [
12••,
31], but lower risk was recently observed in a survey of a large population without previous stroke [
34].
Finally, although RCTs of statins have been negative in advanced heart failure, late-stage renal disease, or dementia, neither have specific harms been detected in these most vulnerable patient groups. In a large real-life database, statins appeared to be similarly tolerated in older (> 75 years) and younger adults in primary prevention [
35]. In accordance, health-related quality of life was similar among home-living octogenarian statin users as compared to nonusers [
36].
Statin Treatment Started in Old Age in Primary Prevention
Meta-analysis of statin trials has revealed that each 1 mmol/L reduction in LDL cholesterol decreases the yearly rate of major ASCVD events by one fifth and total mortality by 10% [
12••]. The relative reduction of ASCVD has been independent of baseline LDL cholesterol level and of various subgroups. With relative risk of ASCVD being constant and absolute risk higher in older people, statin treatment should lead to benefits also in people aged 75 and older. This is clearly the case for secondary prevention according to a meta-analysis of randomized statin trials [
37••]. The meta-analysis included 14,483 participants older than 75 years, and statin treatment was associated with a 15% reduced rate of major vascular events (HR 0.85, 95% CI 0.73–0.98) among those with existing ASCVD.
In primary prevention, direct evidence of benefit in age groups 75 years and over has been less clear in RCTs [
37••]. Observational studies up to 2014 have suggested mixed benefit, and recent observational statin studies (mostly > 75 years, some starting from 70 years) and new analyses of older RCTs in primary prevention are shown in Table
2 [
38‐
43]. Overall, the results are not unequivocal but seem to suggest benefits of starting statin in patients older than 75 years at increased risk of ASCVD, such as diabetics.
Table 2
Recent observational studies and randomized controlled trials of statins in older people without atherosclerotic cardiovascular disease (ASCVD)
Observational studies |
| 1130 statin users were matched to nonusers > 70 years Total n = 7213 | 7 | Primary prevention | All-cause mortality: HR 0.82, 95% CI 0.69–0.98 CVD events: HR 0.86, 95% CI 0.70–1.06 Stroke: HR 0.70, 95% CI 0.45–1.09 In subgroup analyses, results were similar in age groups at baseline (70–76 or > 76 years) or according to functional status. |
| 7502 new statin users were matched to nonusers, > 75 years Total n = 46,864 | 5.6 | Primary prevention |
75–84 year olds without diabetes:
ASCVD: HR 0.94, 95% CI 0.86–1.04 All-cause mortality: HR 0.98, 95% CI 0.91–1.05
85 and older without diabetes
ASCVD: HR 0.93, 0.82–1.06 All-cause mortality: HR 0.97, 95% CI 0.90–1.05
75–84 year olds with diabetes
ASCVD: HR 0.76, 95% CI 0.65–0.89 All-cause mortality: HR 0.84, 95% CI 0.75–0.94
85 and older with diabetes
ASCVD: HR 0.82, 95% CI 0.53–1.26 All-cause mortality: HR 1.05, 95% CI 0.86–1.28 |
| New statin users matched to nonusers, > 75 years. Total n = 7284 | 4.7 | Primary prevention | HR 0.93 (95% CI 0.89–0.96) in people with modifiable risk factors (diabetes or cardiovascular medications). HR 1.01 (95% CI 0.86–1.18) in people without modifiable risk factors |
| 11,017 > 75 years | Nested case–control | Primary prevention | Composite outcome: adjusted OR [AOR] 0.77; 95% CI 0.71–0.84 Stroke: AOR 0.74; 95% CI 0.61–0.89 All-cause death: AOR 0.73; 95% CI 0.66–0.81 |
Kim et al. (SCOPE-75) [ 42] | 639 statin users, 639 statin never users, > 75 years | 5.2 | Primary prevention (but with ASCVD risk factors) | Major adverse cardiovascular and cerebrovascular events: HR 0.59, 95% CI 0.41–0.85. All-cause death: HR 0.56, 95% CI 0.34–0.93. |
Randomized controlled trials |
JUPITER | 5695 > 70 years | 2.2 | Primary prevention | Combined cardiovascular end point: HR 0.61; 95% CI 0.43–0.86; P = 0.004 All-cause mortality: HR 0.80; 95% CI 0.62–1.0; P = 0.09 |
HOPE-3 | 3086 > 70 years | 5.0 | Primary prevention | Combined cardiovascular end point: HR 0.83; 95% CI 0.64–1.07; P = 0.16 All-cause mortality: HR 0.91; 95% CI 0.73–1.13; P = 0.38 |
Meta-analysis of JUPITER and HOPE-3 [ 43] | 8781 > 70 years | | | Composite end point of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death: HR 0.74, 95% CI 0.61–0.91 |
Meta-analysis of statin trials in older people [ 37••] | 14,483 > 75 years | 4.9 | Primary and secondary prevention | Major vascular events: Primary prevention HR 0.92, 95% CI 0.73–1.16 Secondary prevention: HR 0.85, 95% CI 0.73–0.98 |
A clinical trial, STAtin Therapy for Reducing Events in the Elderly (STAREE, NCT02099123), is currently ongoing and enrolling 18,000 participants for a randomized and placebo-controlled trial to determine whether atorvastatin (40 mg daily) will extend the length of a disability-free life (survival outside permanent residential care) among healthy participants aged 70 years and older. The trial has started in 2015 and is expected to close in 2023. Primary outcome measures of STAREE are either (1) death or development of dementia (measured by cognitive function tests) or development of disability (measured by the KATZ ADL test) or (2) a major fatal or non-fatal CVD event. Numerous secondary outcomes, such as quality of life, cognitive decline, frailty, and cost-effectiveness, will also be analyzed.
Oldest-Old
There are no randomized studies about starting statin specifically after 80 or 85 years, and the oldest age groups (including only modest number of individuals) are not separated in trials. According to expert groups of the American National Institutes of Aging (NIA) [
44], prospective, traditional, placebo-controlled, randomized clinical trials, and pragmatic trials would be suitable options to address gaps in knowledge of oldest patients. Accordingly, the experts urge to include better representation of very old adults, women, underrepresented minorities, and individuals with various health status, cognitive, socioeconomic, and educational backgrounds in future trials. However, it may be challenging to recruit oldest patients for a placebo-controlled trial and it is feared that a potentially negative result (like lack of effect of statins in end-stage disease) would be wrongly applied to those older patients, whose treatment has been started earlier in life, simply because of age [
45].