REVIEW URRENT C OPINION
Statins in the elderly: an answered question? Sophia Zoungas a,b, Andrea Curtis a, Andrew Tonkin a, and John McNeil a
Purpose of review A strong potential exists for greater promotion of statin therapy among the over-70 age group on the basis of their high absolute cardiovascular risk. However, the evidence for this approach is currently unclear. Recent findings Meta-analysis of trials highlights the uncertainty about the efficacy of statins in the prevention of major vascular events and all-cause mortality in the elderly. This stems from inadequate numbers of participants from this age group included in previous randomized clinical trials. Adverse effects of statins are likely to be greater in the elderly, but their frequency is uncertain and their contribution to frailty and loss of independence in the elderly has been little studied. Summary Real world trials examining the impact of statin therapy in the elderly are now called for. Keywords adverse events, all-cause mortality, elderly, frailty, primary prevention, statins
INTRODUCTION As we move into the 21st century, the world is experiencing a rapid demographic transition characterized by an immense expansion in the population along with decreasing fertility and increasing life expectancy [1]. In the developed world, increasing survival among older age groups is a major contributor to this shift, with almost twice as many 80-year olds surviving into their 90s, and over double the proportion of 90-year olds surviving to 100 years or more compared with 50 years ago [2]. In the United States, the proportion of the population aged 65 years and over is projected to increase from 40 million in 2009 to 89 million in 2050, with 19 million (20%) in the oldest old age group (85þ) by 2050 [3]. Recent Eurostat projections predict similar scenarios across Europe over the next 50 years [4], with the proportion of the population aged over 65 years predicted to make up over 30% of the population in 17 of 31 European countries (with people aged over 80 years representing more than 10% of the entire population by 2060) [4]. A similar transition is likely to be seen in many other highincome countries [2].
FRAILTY AND NEED FOR RESIDENTIAL CARE IN THE ELDERLY As age advances, quality of life is increasingly affected by frailty, cognitive decline and the consequences of a variety of chronic diseases, including www.co-cardiology.com
cardiovascular disease (CVD), arthritis, osteoporosis and malignancy. Although preventive healthcare has reduced the burden of chronic illness at younger ages, there is limited evidence that these advances have improved health in those aged beyond the mid–late 80s [2]. Given this, a large number of older individuals living in developed nations will ultimately progress to residential care (Fig. 1) [5]. In Australia, at 75 years of age, the remaining lifetime risk of need for residential care is estimated at 72% for women and 53% for men, at a current cost of approximately $7 billion Australian dollars per annum [6]. The greatest component of this cost is for high-level (that is nursing home) care in a residential facility, which is estimated to cost approximately $65 000 Australian dollars per annum per individual [6]. In one report of admissions into residential care, the top first-listed medical conditions, excluding behavioural and mental conditions, were a
School of Public Health and Preventive Medicine, Monash University, Melbourne and bThe George Institute for Global Health, Sydney, Australia Correspondence to Associate Professor Sophia Zoungas, Monash Centre for Health Research and Implementation - MCHRI, School of Public Health & Preventive Medicine, Monash University - in partnership with Monash Health, Melbourne, Victoria 3004, Australia. Tel: +613 9594 7500; fax: +613 9594 7554; e-mail: [email protected] Curr Opin Cardiol 2014, 29:372–380 DOI:10.1097/HCO.0000000000000082 Volume 29 Number 4 July 2014
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Statins in the elderly: an answered question? Zoungas et al.
instance, in the United States, it has been estimated that an average delay of 1 year in the onset of dementia would reduce the number of cases requiring care by 800 000 over 50 years [8].
KEY POINTS Meta-analysis of trials highlights the uncertainty about the efficacy of statins in the prevention of morbidity and mortality in older populations. This may stem from inadequate numbers in this age group included in major trials.
A ROLE FOR STATINS IN THE ELDERLY
Warnings about adverse effects of statins have recently been added to the product information, but their frequency is uncertain, and appears higher in the elderly.
One promising but inadequately tested approach to extending life and maintaining independence in elderly people is use of statin therapy.
A strong potential exists for greater promotion of statin therapy among the over-70 age group on the basis of recent guidelines advocating the use for primary prevention at lower absolute cardiovascular risk levels. Evidence in the elderly is currently insufficient to support this proposal. Real world trials examining the impact of statin therapy in older people are now called for.
Total cholesterol and mortality in the elderly
circulatory system diseases, musculoskeletal and connective tissue disorders, and endocrine, nutritional and other metabolic disorders [7]. Moreover, the most common reason for leaving permanent residential care was death (91%), with about 25% of those who died in residential care having been in care for less than 6 months [7]. Consequently, it has become essential to consider therapies that have the potential to reduce those diseases that cause frailty and the need for residential care, as well as therapies that improve or do not compromise the quality of life of older people. If the requirement for residential aged care could be delayed, even by 1–2 years, then the benefits to society would be substantial. For
In the elderly, the relationship between total cholesterol and all-cause or cause-specific mortality varies. A number of observational studies examining all-cause mortality in the elderly (over 80 years) have reported no association or a predominantly negative association, with the lowest total cholesterol levels associated with the highest all-cause mortality [9–14]. In contrast, the Prospective Studies Collaboration reported a positive linear association between total cholesterol and ischaemic heart disease (IHD) mortality but no significant association between total cholesterol and stroke mortality or other vascular mortality in the elderly [15]. Although the relative effects of total cholesterol on risk of IHD mortality were less at older than younger ages, the absolute effects were much greater [15]. Given the uncertainty around optimal total cholesterol levels in the elderly, the decision as to whether statin therapy should be initiated or even continued in the elderly can only be guided by randomized controlled trials.
Institutions
Home
% of population aged 65 years and over 25 22.1
20
20.3 19.1 17.6 17.4
15
16.7
16.3 14.5 13.1 13.0 12.8 12.7
12.3
11.7
11.2 11.2
10 7.2
5
6.7 6.4 6.4 6.4
5.9 4.1
3.7 3.4 3.2 0.8
Sw Is it rae N zer l et la he nd N ew rla n Ze ds al an N d or D wa en y m S w ark ed C z e Au e n c h str R ali Lu e p u a xe b l m ic bo ur Ja g O pan EC D Fi 21 n G lan er d m an Fr y an H ce un ga r Sp y a U Slo i n ni ve te d nia St a Es tes to ni Ko a re Ic a el an d Ita Ire ly la Sl ov C nd ak a n R ad ep a ub Po lic la nd
0
FIGURE 1. Population aged 65 years and over receiving long-term care, 2011 (or nearest year). Source: OECD Health Statistics 2013, http://dx.doi.org/10.1787/888932315602 [5]. 0268-4705 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
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Lipids and emerging risk factors
Pharmacology/mechanisms of action of statins Statins [3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors] are a class of drugs with the potential to delay the onset of several causes of incapacity in the elderly. Their best-recognized pharmacological action is to inhibit the mevalonate pathway and biosynthesis of cholesterol and isoprenoids by binding to HMG-CoA reductase and displacing the natural substrate HMG-CoA. This interaction prevents HMG-CoA reductase from attaining a functional conformation, stops the conversion of HMG-CoA to l-mevalonate and produces a reduction in intracellular cholesterol [16]. The low-density lipoprotein (LDL)-receptor gene expression and formation on the hepatocyte cell surface are then induced. The result is an increase in extraction of LDL-cholesterol (LDL-C) and its precursors, intermediate-density lipoprotein (IDL) and very-low-density lipoprotein (VLDL), from the blood and decrease in circulating LDL-C concentrations (by 18–55%) [16]. Beneficial effects on other lipid parameters have also been reported, including increased high-density lipoprotein-cholesterol (HDL-C) (by 5–15%) [17], decreased levels of atherogenic lipoproteins [18], decreased triglyceride concentration (7–30%) and decreased synthesis and secretion of triglyceride-rich lipoproteins [18] as well as reduced susceptibility of LDL-C to oxidation [16]. The reduction in circulating lipid levels underpins their ability to reduce the incidence of myocardial infarction and stroke and their long-term sequelae (disability and cognitive decline, among others). In addition, statins exert a number of other pleiotropic effects, including a moderately powerful anti-inflammatory action [19]. The pleiotropic (or cholesterol-independent) effects of statins have been attributed to the inhibition of isoprenoid metabolite formation (geranylgeranyl pyrophosphate and farnesyl pyrophosphate) [16]. These metabolites are intermediates in the posttranslational formation of several cell-signalling proteins that control multiple cell functions, including maintenance of cell shape, motility, factor secretion, differentiation and proliferation, thus explaining improvements in endothelial function, vascular inflammation and oxidation and atherosclerotic plaque stability [16].
Statin effects on major vascular events and all-cause mortality The impact of statin therapy on cardiovascular outcomes has been studied in primary (mostly high-risk) and secondary prevention settings. Supplementary Digital Content 1 (http://links.lww. 374
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com/HCO/A20) provides a summary of studies in the last 2 years reporting on the potential beneficial effects of statin therapy. Notably, a recent meta-analysis of pooled individual data from 22 trials of statin versus control including both high-risk and established CVD patients has reported a 21% reduction in risk of major vascular events (MVE) per 1mmol/l reduction in LDL-C, attributed to reduced risks of major coronary events, stroke events and vascular death [20]. The risk of all-cause mortality was also reduced, albeit to a much lesser extent (10% per 1 mmol/l reduction in LDL-C). No effect on non-vascular deaths was observed. Of note, participants were predominantly middle-aged men with high baseline LDL-C levels (mean weighted LDL-C level 3.7 mmol/l). Analyses by age group (75 years) indicated smaller effect sizes in older participants compared with younger participants. In those with established CVD, the benefits of statin were clear, with risks of MVE and death reduced in people of all ages [20]. Moreover, the number needed to treat is sufficiently low to justify treatment (28 patients would need to be treated for 5 years to prevent one death) [21]. In those without established CVD and without diabetes, the effects of statin on risk of MVE were less clear in those aged 70 years or older, with no data provided on risk of all-cause mortality [20]. In those over 70 years of age, statin therapy did not significantly reduce risk of MVE, with the risk reductions varying from 63% to 21% to 10% in low, medium and high-risk participants, respectively (predominantly primary prevention participants, 5-year predicted MVE risk of 60, 70 years and >70 years). Reproduced with permission from [20].
around one-tenth had diabetes; in comparison, JUPITER was a primary prevention trial undertaken in people with no hyperlipidemia but with high C-reactive protein levels [22,23]. Furthermore, in PROSPER, there was a smaller (34%) reduction in LDL-C with statin therapy compared with placebo, whereas in JUPITER, final median LDL-C levels with statin therapy were much lower, half the levels observed in the placebo group [22,23]. The JUPITER exploratory analyses also reported no significant interaction between age and treatment effect for
any outcome [23]. Early termination of JUPITER, after 1.9 years of follow-up, may have led to overestimation of the benefits. Given the proportional effects of total cholesterol on MVE decline with age, such that greater relative risks are observed in younger people [aged 55–64 years: relative risk (RR) IHD 1.44, 95% CI 1.29–1.61; RR ischaemic stroke 1.20, 95% CI 1.15–1.25)] compared with older people (aged 75–84 years: RR IHD 1.18, 95% CI 1.16–1.21; RR ischaemic stroke 1.03, 95% CI 0.85–1.25) [24], and
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Lipids and emerging risk factors
meta-analyses of statin trials report highly significant effects in younger people (70 years) [20,25], uncertainty about the benefits of statins in otherwise healthy older people remains.
Statin effects on other clinical outcomes Although most studies focus on cardiovascular effects, statin therapy may be associated with other benefits that are potentially of importance in the elderly.
Dementia and Parkinson’s disease A number of meta-analyses of both randomized controlled trials and observational studies have addressed the role of statins in prevention or treatment of dementia (see Supplementary Digital Content 1, http://links.lww.com/HCO/A20) [26 ,27 , 28,29]. In a meta-analysis of observational studies, statin therapy was associated with reduction in risk of dementia, Alzheimer’s disease and mild cognitive impairment [28]. Among patients without cognitive impairment at baseline, long-term statin therapy was associated with a 29% relative reduction in incident dementia [29]. Similarly, a recent metaanalysis of 11 observational studies demonstrated a protective effect of statins on the risk of Parkinson’s disease (RR 0.77, 95% CI 0.64–0.92, P ¼ 0.005) [30]. Despite this, long-term statin use was not significantly associated with the risk of Parkinson’s disease (RR 0.72, 95% CI 0.45–1.13, P ¼ 0.15). Controlled clinical trials are required to further explain this association. &&
&&
Bone density and fracture incidence Cohort studies driven by experimental evidence suggesting statin therapy inhibits osteoclast formation and bone resorption have reported increased bone mineral density and decreased fracture risk for people using statins compared with those not using statins [odds ratio (OR) 0.77, 95% CI 0.60–1.00] [31,32]. In contrast, limited data from randomized controlled trials have suggested no effect of statins on fracture risk (OR 1.03, 95% CI 0.91–1.16) [32]. More definitive results from trials designed to evaluate statin use and fracture risk in high-risk elderly patients are needed.
Frailty, institutionalization and health service utilization Frailty, defined as an excess vulnerability to stressors with reduced ability to maintain/regain premorbid 376
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function after an insult and characterized by slowness, weakness, fatigue, weight loss and low activity, is increasingly being recognized as related to and distinct from other diseases [33]. Importantly, frailty has been independently associated with falls, hospitalization and mortality in the elderly [34]. To date, few statin trials have examined frailty or frailty-specific outcomes. Of note, the PROSPER trial reported no effect of statin therapy on daily activity levels (as quantified by the Barthel index or the Instrumental Activities of Daily Living Questionnaire) in men and women aged between 70 and 82 years [22]. A few key observational studies have also examined frailty and institutionalization in the elderly. The Women’s Health Initiative observational study reported a similar incidence of frailty in current statin users and nonusers [35], the Concord Health and Ageing in Men project reported no significant association between statin use and institutionalization [36 ], and a large administrative database review indicated no reduction in health service utilization in older patients after hospitalization for ischaemic heart disease and commencement of statin [37]. &
STATINS IN THE ELDERLY: POTENTIAL RISKS The likelihood of adverse effects of drug therapy increases in older people [38]. This may be related to changes in metabolic processes and development of concomitant diseases such as chronic kidney disease (CKD), which makes the elderly much more vulnerable to drug interactions and statin toxicity. Much of the knowledge of specific adverse effects comes from spontaneous reports or from trials in a younger age group. Supplementary Digital Content 2 (http://links.lww.com/HCO/A21) provides a summary of studies highlighted in the last 2 years as reporting on the potential adverse effects of statin therapy. As with efficacy, the adverse effect burden of statins in older individuals has not been well studied. As a result, it is not possible to know the balance of risks and benefits associated with the use of these agents in the older age group [39]. Among the elderly, the issues most likely to influence the risk/benefit balance are myopathy, diabetes, cancer and cognitive impairment.
Myopathy All statins have been reported to cause myopathy, with the severity ranging from asymptomatic increases in creatine kinase to muscle aches and weakness to fatal rhabdomyolysis [40]. The precise mechanisms are not well understood, dose-dependent and Volume 29 Number 4 July 2014
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Statins in the elderly: an answered question? Zoungas et al.
may occur even after therapy has been tolerated for up to 1 year [41]. The estimated incidence of statin myopathy in trials has ranged from 1.4 to 5% [42] with the lowest rates reported for atorvastatin at low or high dosage [43]. Older age, female sex, concomitant use of inhibitors of cytochrome P450 3A4 and hypothyroidism are recognized risk factors for the development of statin myopathy [44]. Vitamin D may also have a role in statin-induced myopathy, although this is uncertain [45].
Diabetes In a recently published meta-analysis of statin trials, statin use was associated with a 9% increased risk for incident diabetes, with little heterogeneity between trials [46]. Meta-regression indicated that the risk of developing diabetes was highest in trials with older participants but also in those with risk factors of the metabolic syndrome [46]. Given that the absolute risk of type 2 diabetes is strongly dependent on age [47], the adverse impact of statin therapy for this group may be greater. In view of these data, the Federal Drug Administration (FDA) in 2012 modified the labelling of statins to include a warning for the potential risk of increased blood sugar levels and new type 2 diabetes [48].
Cancer The PROSPER trial reported an increased risk of cancer and cancer mortality with statin therapy among men and women older than 70 years [22]. This effect was not observed by other statin trials and was incongruent with earlier in-vitro and in-vivo experiments, which suggested that statins may inhibit tumour cell growth [31]. A metaanalysis of all statin trials suggested no overall increased risk of cancer or cancer mortality over an average follow-up of 4.8 years, albeit in a mostly middle-aged population [49]. Nonetheless, more data on the effects of statin therapy on risk of cancer in elderly patients (70–82 years) are required and further follow-up studies have been called for in such patients [39]. Longer follow-up would determine whether new cancer events could occur with time. This is especially important if statin therapy is to be advocated for primary prevention.
Cognitive impairment The FDA recently reported an analysis of the US spontaneous reporting database, FDA Adverse Event Reporting System (AERS), the published medical literature (case reports and observational studies) and randomized clinical trials to evaluate the effect of statin therapy on cognition [48]. The postmarketing adverse event reports generally described ill-defined memory loss that was reversible upon
discontinuation of statin. Most reports were from individuals over the age of 50 years. Time to onset of the impairment was highly variable, ranging from 1 day to years after statin exposure. An association between cognitive impairment and a specific statin, a specific age group, a particular statin dose or concomitant medication use was not observed. Furthermore, the cognitive impairment did not appear to be associated with fixed or progressive dementia, such as Alzheimer’s disease, and was not detectable in clinical trials measuring longer-term cognitive function using combinations of neurocognitive tests such as Mini-mental state examination (MMSE), digit test and Stroop test [22,26 ,27 ]. Nonetheless, in 2012, the FDA modified the labelling of statins to include a warning for the potential risk of cognitive effects such as memory loss and confusion [48]. &&
&&
STATIN UTILIZATION Statins are one of the most frequently dispensed drugs in the United States [50]. The British Heart Foundation reported that, in 2011, one million statin prescriptions were provided each week in England [51]. At present, statin use in the elderly is lower than expected given the high absolute risk of this population. A UK survey of 41 250 GP medical records reported that 23% of patients aged 75 years or older with no history of CVD were prescribed statin therapy compared with 29% in the 70–74-year age group [52 ]. Among patients aged 75 years or older, for every 5-year increment in age, the odds of being prescribed a statin decreased compared with the 40–44-year age group. Similarly, one US study reported that 22% of people aged 80 years or older (in a primary prevention setting) were prescribed a statin [53 ] and another reported that those aged 65–69 years were more likely to use a statin than those aged 70 years or older [54 ]. &
&
&
IMPLICATIONS OF GUIDELINES FOR TREATMENT OF ELEVATED CHOLESTEROL IN THE ELDERLY The potential for greater use of statins among older people is illustrated by Fig. 3a and b. This provides an approximation of the proportion of each age group in which the absolute cardiovascular risk exceeds a 15% likelihood of a new vascular event in the next 5 years (commonly regarded as the fundamental indication for statin therapy) [55]. It is based on the cardiovascular death rate reported in the West of Scotland Coronary Prevention Study (WOSCOPS) multiplied by four, as there were four incident cardiovascular events for each fatal
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Lipids and emerging risk factors
Percentile of 10-year CHD mortality risk
(a)
Age 30–34
35–39
40–44
45–49
50–54
55–59
60–64
65–69
70–74
75–79
80–84
85+
SUM CHD deaths
2–5 6–10 11–15 16–20 21–25 26–30 31–35 36–40 41–45 46–50 41–55 56–60 61–65 66–70 71–75 76–80 81–85 86–90 91–95 96–100 SUM
0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 2 2 2 12
0 0 0 1 1 1 1 1 1 1 1 2 2 2 2 3 3 4 5 6 37
1 1 1 2 2 2 2 3 3 3 3 4 4 4 5 5 6 8 11 14 84
2 2 3 3 4 4 5 5 6 6 7 7 8 9 10 11 13 16 19 22 162
4 5 6 7 7 8 9 10 11 11 12 13 14 16 18 20 23 28 33 39 294
7 9 10 12 13 14 15 16 17 18 19 21 22 24 26 29 33 39 45 52 441
9 12 14 16 18 19 21 22 24 25 27 29 31 34 37 42 48 57 66 75 626
13 16 18 21 23 25 27 30 32 34 37 40 43 47 51 56 62 72 82 92 821
21 25 29 32 36 39 41 44 45 48 51 55 58 63 67 73 79 89 99 109 1103
38 44 50 54 57 59 62 65 68 71 75 79 84 88 94 102 111 124 141 158 1624
54 61 69 76 82 88 93 97 101 105 110 115 120 126 133 141 150 161 173 185 2240
54 64 73 83 91 98 104 109 114 119 124 129 133 139 145 153 162 174 187 199 2454
102 109 116 123 128 133 140 147 154 160 166 171 176 182 189 197 210 236 263 290 3392
305 348 389 430 462 490 520 549 576 601 632 666 696 735 778 833 901 1010 1126 1243 13290
% of all CHD deaths
0%
0%
1%
1%
2%
3%
4%
6%
8%
12%
17%
18%
26%
80–84
85+
(b)
Percentile of 10-year CHD mortality risk
% of all
25–29
2% 3% 3% 3% 3% 4% 4% 4% 4% 5% 5% 5% 5% 6% 6% 6% 7% 8% 8% 9%
Age 25–29
30–34
35–39
40–44
45–49
50–54
55–59
60–64
65–69
70–74
75–79
% of all
SUM CHD deaths
1–5
0
0
0
0
1
1
2
3
6
13
24
46
123
219
2%
6–10
0
0
0
0
1
1
2
4
8
15
28
53
150
262
2%
11–15
0
0
0
1
1
1
3
5
10
17
31
61
176
306
3%
16–20
0
0
0
1
1
2
3
5
11
20
35
69
202
349
3%
21–25
0
0
0
1
1
2
3
6
12
22
38
75
223
383
3%
26–30
0
0
0
1
1
2
4
7
13
24
42
82
239
415
4%
31–35
0
0
0
1
1
2
4
8
14
26
45
87
254
442
4%
36–40
0
0
0
1
2
3
4
8
15
28
47
91
268
467
4%
41–45
0
0
0
1
2
3
5
9
16
31
51
95
283
496
4%
46–50
0
0
0
1
2
3
5
9
16
33
55
100
301
525
4%
51–55
0
0
1
1
2
3
6
9
17
36
60
105
323
563
5%
56–60
0
0
1
1
3
4
6
10
18
37
67
112
346
605
5%
61–65
0
0
1
2
3
4
7
10
19
39
75
120
367
647
6%
66–70
0
0
1
2
3
5
7
11
21
41
84
129
382
686
6%
71–75
0
1
1
2
4
5
8
12
23
44
93
140
391
724
6%
76–80
0
1
1
2
4
6
9
14
25
49
103
152
397
763
6%
81–85
0
1
1
3
5
7
11
17
27
55
115
167
406
815
7%
86–90
0
1
2
4
6
10
14
20
33
65
134
194
430
913
8%
91–95
1
1
3
5
8
12
19
26
41
79
153
221
455
1024
9%
96–100
1
1
3
6
10
14
24
32
51
93
172
249
482
1138
10%
11742
SUM
2
6
15
36
61
90
146
225
396
767
1452
2348
6198
% of all CHD deaths
0%
0%
0%
0%
1%
1%
1%
2%
3%
7%
12%
20%
53%
FIGURE 3. The proportion of each age group in each absolute cardiovascular risk stratum for (a) males and (b) females. The shaded section under the thick black line shows the approximate percentage of each age group with a risk of 15% of developing a cardiovascular event in the next 5 years. The different shades of blue show the proportions with a 5, 10, 15 and 20% risk.
event in this study [56]. On this basis, most males over the age of 75 years, and a high percentage of females, would qualify for consideration of statin therapy. Greater use of statins is also likely to be driven by the recent change in the American College of Cardiology/American Heart Association guidelines on the treatment of cholesterol to reduce vascular events, which have caused controversy by now 378
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recommending moderate-to-high-intensity statin therapy for people aged 40–75 years at much lower absolute risk (i.e. 10-year absolute cardiovascular risk of 7.5% or higher compared with 20% or higher in previous guidelines), with no requirement for monitoring of lipid levels [57 ]. This change would appear premature in the elderly, in whom an absence of clear evidence on the benefits versus the adverse effects continues to be an issue for statin therapy, as &&
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Statins in the elderly: an answered question? Zoungas et al.
highlighted by the recent literature (Supplementary Digital Content 1 and 2).
REFERENCES AND RECOMMENDED READING
NEED FOR FURTHER RESEARCH
Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest
Given the potential for widespread use of statins amongst the elderly, more certainty about the scale of any likely benefit is needed. Although a reduced age-specific incidence of CVD, stroke and vascular dementia might well be enough to prevent frailty and delay the need for residential care, the time for a real world trial examining the impact of statin therapy has now arrived. The STAtins for Reducing Events in the Elderly (STAREE) trial will be the first randomized controlled trial of statin therapy in an apparently healthy elderly cohort living independently in the community. STAREE will determine the effects of statin therapy versus placebo on overall survival (all-cause death) or disability-free survival (need for permanent residential care) over an average 5-year treatment period amongst approximately 12 000 elderly Australians (70 years). STAREE will be conducted in Australian general practice and utilize the resources and expertise in communitybased research. This study has the potential to influence the care of elderly people in countries across the developed world and to change the way that preventive drugs are evaluated in this age group.
CONCLUSION Meta-analysis of trials highlights the uncertainty about the efficacy of statins in the prevention of morbidity and mortality in older populations. This may stem from inadequate numbers in this age group included in major trials. Warnings about adverse effects of statins have recently been added to the product information, but their frequency is uncertain, and appears higher in the elderly. Real world trials examining the impact of statin therapy in older people are now called for. STAREE will determine the effects of statin therapy versus placebo on overall survival (all-cause death) or disability-free survival (need for permanent residential care) over an average 5-year treatment period among the elderly (70 years). Acknowledgements None. Conflicts of interest S.Z. is supported by a Heart Foundation of Australia Career Development Fellowship. All authors had access to the data and played a role in writing this article. S.Z. has served on advisory boards and/or received honoraria for speaking engagements from MSD, Amgen, Astra Zeneca and BMS.
1. Bongaarts J. Human population growth and the demographic transition. Philos Trans R Soc Lond B Biol Sci 2009; 364:2985–2990. 2. Christensen K, Doblhammer G, Rau R, Vaupel JW. Ageing populations: the challenges ahead. Lancet 2009; 374:1196–1208. 3. Jacobsen L, Mather M, Lee M, Kent M. America’s aging population. Population Bulletin 2011; 66:2–3. 4. Lanzieri G. The greying of the baby boomers, a century-long view of ageing in European populations. Eurostat Statistics Focus 2011; 6–7. 5. OECD (2013), Health at a Glance 2013: OECD Indicators, OECD Publishing. http://dx.doi.org/10.1787/health_glance-2013-en. 6. Productivity Commission 2011. Caring for Older Australians: Overview, Report No. 53, Final Inquiry Report, Canberra. 7. Australian Institute of Health and Welfare 2012. Residential aged care in Australia 2010-11: a statistical overview. Aged care statistics series no. 36. Cat. no. AGE 68. Canberra: AIHW. 8. Brookmeyer R, Gray S, Kawas C. Projections of Alzheimer’s disease in the United States and the public health impact of delaying disease onset. Am J Public Health 1998; 88:1337–1342. 9. Jonsson A, Sigvaldason H, Sigfusson N. Total cholesterol and mortality after age 80 years. Lancet 1997; 350:1778–1779. doi: 10.1016/s0140-6736 (05)63609-4. 10. Schatz IJ, Masaki K, Yano K, et al. Cholesterol and all-cause mortality in elderly people from the Honolulu Heart Program: a cohort study. Lancet 2001; 358:351–355. 11. Volpato S, Leveille SG, Corti MC, et al. The value of serum albumin and high-density lipoprotein cholesterol in defining mortality risk in older persons with low serum cholesterol. J Am Geriatr Soc 2001; 49:1142– 1147. 12. Weverling-Rijnsburger AW, Jonkers IJ, van Exel E, et al. High-density vs lowdensity lipoprotein cholesterol as the risk factor for coronary artery disease and stroke in old age. Arch Int Med 2003; 163:1549–1554. 13. Foody JM, Wang Y, Kiefe CI, et al. Long-term prognostic importance of total cholesterol in elderly survivors of an acute myocardial infarction: the Cooperative Cardiovascular Pilot Project. J Am Geriatr Soc 2003; 51:930– 936. 14. Schupf N, Costa R, Luchsinger J, et al. Relationship between plasma lipids and all-cause mortality in nondemented elderly. J Am Geriatr Soc 2005; 53:219–226. 15. Lewington S, Whitlock G, Clarke R, et al. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55 000 vascular deaths. Lancet 2007; 370:1829–1839. 16. Stancu C, Sima A. Statins: mechanism of action and effects. J Cell Mol Med 2001; 5:378–387. 17. Nicholls SJ, Tuzcu EM, Sipahi I, et al. Statins, high-density lipoprotein cholesterol, and regression of coronary atherosclerosis. JAMA 2007; 297: 499–508. 18. Maron DJ, Fazio S, Linton MF. Current perspectives on statins. Circulation 2000; 101:207–213. 19. Greenwood J, Mason JC. Statins and the vascular endothelial inflammatory response. Trends Immunol 2007; 28:88–98. 20. Mihaylova B, Emberson J, Blackwell L, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: metaanalysis of individual data from 27 randomised trials. Lancet 2012; 380:581– 590. 21. Afilalo J, Duque G, Steele R, et al. Statins for secondary prevention in elderly patients: a hierarchical bayesian meta-analysis. J Am Coll Cardiol 2008; 51:37–45. 22. Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002; 360:1623–1630. 23. Glynn RJ, Koenig W, Nordestgaard BG, et al. Rosuvastatin for primary prevention in older persons with elevated C-reactive protein and low to average low-density lipoprotein cholesterol levels: exploratory analysis of a randomized trial. Ann Int Med 2010; 152:488–496. 24. Singh GM, Danaei G, Farzadfar F, et al. The age-specific quantitative effects of metabolic risk factors on cardiovascular diseases and diabetes: a pooled analysis. PLoS One 2013; 8:e65174. 25. Savarese G, Gotto AM Jr, Paolillo S, et al. Benefits of statins in elderly subjects without established cardiovascular disease: a meta-analysis. J Am Coll Cardiol 2013; 62:2090–2099. 26. McGuinness B, O’Hare J, Craig D, et al. Cochrane review on ‘Statins for the && treatment of dementia’. Int J Geriatr Psychiatry 2013; 28:119–126. Cochrane systematic review of three double-blind randomized controlled trials of statin therapy in people diagnosed with dementia. Demonstrated lack of benefit of statins compared with placebo on cognitive measures.
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Lipids and emerging risk factors 27. Pandey RD, Gupta PP, Jha D, Kumar S. Role of statins in Alzheimer’s disease: a retrospective meta-analysis for commonly investigated clinical parameters in RCTs. Int J Neurosci 2013; 123:521–525. This is the meta-analysis of five randomized controlled trials of statins in patients with Alzheimer’s disease. Only MMSE score showed a significant difference in favour of statins; however, the data were highly heterogeneous. 28. Richardson K, Schoen M, French B, et al. Statins and cognitive function: a systematic review. Ann Int Med 2013; 159:688–697. 29. Swiger KJ, Manalac RJ, Blumenthal RS, et al. Statins and cognition: a systematic review and meta-analysis of short- and long-term cognitive effects. Mayo Clin Proc 2013; 88:1213–1221. 30. Undela K, Gudala K, Malla S, Bansal D. Statin use and risk of Parkinson’s disease: a meta-analysis of observational studies. J Neurol 2013; 260:158– 165. 31. Bellosta S, Ferri N, Bernini F, et al. Nonlipid-related effects of statins. Ann Med 2000; 32:164–176. 32. Toh S, Hernandez-Diaz S. Statins and fracture risk. A systematic review. Pharmacoepidemiol Drug Saf 2007; 16:627–640. 33. Walston J, Hadley EC, Ferrucci L, et al. Research agenda for frailty in older adults: toward a better understanding of physiology and etiology: summary from the American Geriatrics Society/National Institute on Aging Research Conference on Frailty in Older Adults. J Am Geriatr Soc 2006; 54:991–1001. 34. Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci 2001; 56:M146–M156. 35. LaCroix AZ, Gray SL, Aragaki A, et al. Statin use and incident frailty in women aged 65 years or older: prospective findings from the Women’s Health Initiative Observational Study. J Gerontol A Biol Sci Med Sci 2008; 63: 369–375. 36. Gnjidic D, Le Couteur DG, Blyth FM, et al. Statin use and clinical outcomes in & older men: a prospective population-based study. BMJ Open 2013; 3. This is a prospective cohort study of 1665 community-dwelling men aged 70 years or older participating in the Concord Health and Ageing in Men Project. It suggested no significant association between statin use and institutionalization or death. 37. Cooke CA, Kirkland SA, Sketris IS, Cox J. The impact of statins on health services utilization and mortality in older adults discharged from hospital with ischemic heart disease: a cohort study. BMC Health Serv Res 2009; 9:198. 38. Routledge PA, O’Mahony MS, Woodhouse KW. Adverse drug reactions in elderly patients. Br J Clin Pharmacol 2004; 57:121–126. 39. Brugts JJ, Yetgin T, Hoeks SE, et al. The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: metaanalysis of randomised controlled trials. BMJ 2009; 338:b2376. 40. Bellosta S, Paoletti R, Corsini A. Safety of statins: focus on clinical pharmacokinetics and drug interactions. Circulation 2004; 109 (23 Suppl 1):III50– III57. 41. Graham DJ, Staffa JA, Shatin D, et al. Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA 2004; 292:2585– 2590. 42. Joy TR, Hegele RA. Narrative review: statin-related myopathy. Ann Int Med 2009; 150:858–868. 43. Davidson MH, Robinson JG. Safety of aggressive lipid management. J Am Coll Cardiol 2007; 49:1753–1762. 44. Sathasivam S. Statin induced myotoxicity. Eur J Intern Med 2012; 23:317– 324.
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45. Gupta A, Thompson PD. The relationship of vitamin D deficiency to statin myopathy. Atherosclerosis 2011; 215:23–29. 46. Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 2010; 375:735– 742. 47. Hippisley-Cox J, Coupland C, Robson J, et al. Predicting risk of type 2 diabetes in England and Wales: prospective derivation and validation of QDScore. BMJ 2009; 338:b880. 48. FDA drug safety communication: Important safety label changes to cholesterol-lowering statin drugs. http://www.fda.gov/Drugs/DrugSafety/ ucm293101.htm. [Accessed 16 March 2013] 49. Emberson JR, Kearney PM, Blackwell L, et al. Lack of effect of lowering LDL cholesterol on cancer: meta-analysis of individual data from 175 000 people in 27 randomised trials of statin therapy. PloS One 2012; 7:e29849. 50. Lindsley CW. 2012 trends and statistics for prescription medications in the United States: CNS therapeutics continue to hold leading positions. ACS Chem Neurosci 2013; 4:1133–1135. 51. Trusler D. Statin prescriptions in UK now total a million each week. BMJ 2011; 343:d4350. 52. Sheppard JP, Singh S, Fletcher K, et al. Impact of age and sex on primary & preventive treatment for cardiovascular disease in the West Midlands, UK: cross sectional study. BMJ 2012; 345:e4535. This was a cross-sectional survey of 41 250 GP medical records undertaken in the UK. The results indicated low use of statins for primary prevention among older people. 53. Chokshi NP, Messerli FH, Sutin D, et al. Appropriateness of statins in patients & aged > / ¼ 80 years and comparison to other age groups. Am J Cardiol 2012; 110:1477–1481. This was a retrospective examination of 89 086 electronic health records between 2004 and 2009 from a large health system in Pennsylvania. It included records of 22 646 patients aged at least 80 years and aimed to describe use of statins in the elderly and to determine the clinical factors guiding statin use in that population. A significant proportion of patients over 80 years were prescribed statins for primary prevention. 54. Robinson JG, Booth B. Statin use and lipid levels in older adults: National & Health and Nutrition Examination Survey, 2001 to 2006. J Clin Lipidol 2010; 4:483–490. An analysis of 2006 National Health and Nutrition Examination Surveys that described patterns of statin use in subgroups of elderly people. 55. National Vascular Disease Prevention Alliance. Guidelines for the management of absolute cardiovascular disease risk. 2012. 56. Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med 1995; 333:1301–1307. 57. Stone NJ, Robinson J, Lichtenstein AH, et al. ACC/AHA Guideline on the && Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2013. [Epub ahead of print] These are the new US guidelines for the management of cardiovascular risk in primary prevention for individuals between 40 and 75 years. They developed a new cardiovascular risk calculator based on four American population cohorts.
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Statins in the elderly: an answered question? Sophia Zoungas a,b, Andrea Curtis a, Andrew Tonkin a, and John McNeil a
Purpose of review A strong potential exists for greater promotion of statin therapy among the over-70 age group on the basis of their high absolute cardiovascular risk. However, the evidence for this approach is currently unclear. Recent findings Meta-analysis of trials highlights the uncertainty about the efficacy of statins in the prevention of major vascular events and all-cause mortality in the elderly. This stems from inadequate numbers of participants from this age group included in previous randomized clinical trials. Adverse effects of statins are likely to be greater in the elderly, but their frequency is uncertain and their contribution to frailty and loss of independence in the elderly has been little studied. Summary Real world trials examining the impact of statin therapy in the elderly are now called for. Keywords adverse events, all-cause mortality, elderly, frailty, primary prevention, statins
INTRODUCTION As we move into the 21st century, the world is experiencing a rapid demographic transition characterized by an immense expansion in the population along with decreasing fertility and increasing life expectancy [1]. In the developed world, increasing survival among older age groups is a major contributor to this shift, with almost twice as many 80-year olds surviving into their 90s, and over double the proportion of 90-year olds surviving to 100 years or more compared with 50 years ago [2]. In the United States, the proportion of the population aged 65 years and over is projected to increase from 40 million in 2009 to 89 million in 2050, with 19 million (20%) in the oldest old age group (85þ) by 2050 [3]. Recent Eurostat projections predict similar scenarios across Europe over the next 50 years [4], with the proportion of the population aged over 65 years predicted to make up over 30% of the population in 17 of 31 European countries (with people aged over 80 years representing more than 10% of the entire population by 2060) [4]. A similar transition is likely to be seen in many other highincome countries [2].
FRAILTY AND NEED FOR RESIDENTIAL CARE IN THE ELDERLY As age advances, quality of life is increasingly affected by frailty, cognitive decline and the consequences of a variety of chronic diseases, including www.co-cardiology.com
cardiovascular disease (CVD), arthritis, osteoporosis and malignancy. Although preventive healthcare has reduced the burden of chronic illness at younger ages, there is limited evidence that these advances have improved health in those aged beyond the mid–late 80s [2]. Given this, a large number of older individuals living in developed nations will ultimately progress to residential care (Fig. 1) [5]. In Australia, at 75 years of age, the remaining lifetime risk of need for residential care is estimated at 72% for women and 53% for men, at a current cost of approximately $7 billion Australian dollars per annum [6]. The greatest component of this cost is for high-level (that is nursing home) care in a residential facility, which is estimated to cost approximately $65 000 Australian dollars per annum per individual [6]. In one report of admissions into residential care, the top first-listed medical conditions, excluding behavioural and mental conditions, were a
School of Public Health and Preventive Medicine, Monash University, Melbourne and bThe George Institute for Global Health, Sydney, Australia Correspondence to Associate Professor Sophia Zoungas, Monash Centre for Health Research and Implementation - MCHRI, School of Public Health & Preventive Medicine, Monash University - in partnership with Monash Health, Melbourne, Victoria 3004, Australia. Tel: +613 9594 7500; fax: +613 9594 7554; e-mail: [email protected] Curr Opin Cardiol 2014, 29:372–380 DOI:10.1097/HCO.0000000000000082 Volume 29 Number 4 July 2014
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Statins in the elderly: an answered question? Zoungas et al.
instance, in the United States, it has been estimated that an average delay of 1 year in the onset of dementia would reduce the number of cases requiring care by 800 000 over 50 years [8].
KEY POINTS Meta-analysis of trials highlights the uncertainty about the efficacy of statins in the prevention of morbidity and mortality in older populations. This may stem from inadequate numbers in this age group included in major trials.
A ROLE FOR STATINS IN THE ELDERLY
Warnings about adverse effects of statins have recently been added to the product information, but their frequency is uncertain, and appears higher in the elderly.
One promising but inadequately tested approach to extending life and maintaining independence in elderly people is use of statin therapy.
A strong potential exists for greater promotion of statin therapy among the over-70 age group on the basis of recent guidelines advocating the use for primary prevention at lower absolute cardiovascular risk levels. Evidence in the elderly is currently insufficient to support this proposal. Real world trials examining the impact of statin therapy in older people are now called for.
Total cholesterol and mortality in the elderly
circulatory system diseases, musculoskeletal and connective tissue disorders, and endocrine, nutritional and other metabolic disorders [7]. Moreover, the most common reason for leaving permanent residential care was death (91%), with about 25% of those who died in residential care having been in care for less than 6 months [7]. Consequently, it has become essential to consider therapies that have the potential to reduce those diseases that cause frailty and the need for residential care, as well as therapies that improve or do not compromise the quality of life of older people. If the requirement for residential aged care could be delayed, even by 1–2 years, then the benefits to society would be substantial. For
In the elderly, the relationship between total cholesterol and all-cause or cause-specific mortality varies. A number of observational studies examining all-cause mortality in the elderly (over 80 years) have reported no association or a predominantly negative association, with the lowest total cholesterol levels associated with the highest all-cause mortality [9–14]. In contrast, the Prospective Studies Collaboration reported a positive linear association between total cholesterol and ischaemic heart disease (IHD) mortality but no significant association between total cholesterol and stroke mortality or other vascular mortality in the elderly [15]. Although the relative effects of total cholesterol on risk of IHD mortality were less at older than younger ages, the absolute effects were much greater [15]. Given the uncertainty around optimal total cholesterol levels in the elderly, the decision as to whether statin therapy should be initiated or even continued in the elderly can only be guided by randomized controlled trials.
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FIGURE 1. Population aged 65 years and over receiving long-term care, 2011 (or nearest year). Source: OECD Health Statistics 2013, http://dx.doi.org/10.1787/888932315602 [5]. 0268-4705 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
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Lipids and emerging risk factors
Pharmacology/mechanisms of action of statins Statins [3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors] are a class of drugs with the potential to delay the onset of several causes of incapacity in the elderly. Their best-recognized pharmacological action is to inhibit the mevalonate pathway and biosynthesis of cholesterol and isoprenoids by binding to HMG-CoA reductase and displacing the natural substrate HMG-CoA. This interaction prevents HMG-CoA reductase from attaining a functional conformation, stops the conversion of HMG-CoA to l-mevalonate and produces a reduction in intracellular cholesterol [16]. The low-density lipoprotein (LDL)-receptor gene expression and formation on the hepatocyte cell surface are then induced. The result is an increase in extraction of LDL-cholesterol (LDL-C) and its precursors, intermediate-density lipoprotein (IDL) and very-low-density lipoprotein (VLDL), from the blood and decrease in circulating LDL-C concentrations (by 18–55%) [16]. Beneficial effects on other lipid parameters have also been reported, including increased high-density lipoprotein-cholesterol (HDL-C) (by 5–15%) [17], decreased levels of atherogenic lipoproteins [18], decreased triglyceride concentration (7–30%) and decreased synthesis and secretion of triglyceride-rich lipoproteins [18] as well as reduced susceptibility of LDL-C to oxidation [16]. The reduction in circulating lipid levels underpins their ability to reduce the incidence of myocardial infarction and stroke and their long-term sequelae (disability and cognitive decline, among others). In addition, statins exert a number of other pleiotropic effects, including a moderately powerful anti-inflammatory action [19]. The pleiotropic (or cholesterol-independent) effects of statins have been attributed to the inhibition of isoprenoid metabolite formation (geranylgeranyl pyrophosphate and farnesyl pyrophosphate) [16]. These metabolites are intermediates in the posttranslational formation of several cell-signalling proteins that control multiple cell functions, including maintenance of cell shape, motility, factor secretion, differentiation and proliferation, thus explaining improvements in endothelial function, vascular inflammation and oxidation and atherosclerotic plaque stability [16].
Statin effects on major vascular events and all-cause mortality The impact of statin therapy on cardiovascular outcomes has been studied in primary (mostly high-risk) and secondary prevention settings. Supplementary Digital Content 1 (http://links.lww. 374
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com/HCO/A20) provides a summary of studies in the last 2 years reporting on the potential beneficial effects of statin therapy. Notably, a recent meta-analysis of pooled individual data from 22 trials of statin versus control including both high-risk and established CVD patients has reported a 21% reduction in risk of major vascular events (MVE) per 1mmol/l reduction in LDL-C, attributed to reduced risks of major coronary events, stroke events and vascular death [20]. The risk of all-cause mortality was also reduced, albeit to a much lesser extent (10% per 1 mmol/l reduction in LDL-C). No effect on non-vascular deaths was observed. Of note, participants were predominantly middle-aged men with high baseline LDL-C levels (mean weighted LDL-C level 3.7 mmol/l). Analyses by age group (75 years) indicated smaller effect sizes in older participants compared with younger participants. In those with established CVD, the benefits of statin were clear, with risks of MVE and death reduced in people of all ages [20]. Moreover, the number needed to treat is sufficiently low to justify treatment (28 patients would need to be treated for 5 years to prevent one death) [21]. In those without established CVD and without diabetes, the effects of statin on risk of MVE were less clear in those aged 70 years or older, with no data provided on risk of all-cause mortality [20]. In those over 70 years of age, statin therapy did not significantly reduce risk of MVE, with the risk reductions varying from 63% to 21% to 10% in low, medium and high-risk participants, respectively (predominantly primary prevention participants, 5-year predicted MVE risk of 60, 70 years and >70 years). Reproduced with permission from [20].
around one-tenth had diabetes; in comparison, JUPITER was a primary prevention trial undertaken in people with no hyperlipidemia but with high C-reactive protein levels [22,23]. Furthermore, in PROSPER, there was a smaller (34%) reduction in LDL-C with statin therapy compared with placebo, whereas in JUPITER, final median LDL-C levels with statin therapy were much lower, half the levels observed in the placebo group [22,23]. The JUPITER exploratory analyses also reported no significant interaction between age and treatment effect for
any outcome [23]. Early termination of JUPITER, after 1.9 years of follow-up, may have led to overestimation of the benefits. Given the proportional effects of total cholesterol on MVE decline with age, such that greater relative risks are observed in younger people [aged 55–64 years: relative risk (RR) IHD 1.44, 95% CI 1.29–1.61; RR ischaemic stroke 1.20, 95% CI 1.15–1.25)] compared with older people (aged 75–84 years: RR IHD 1.18, 95% CI 1.16–1.21; RR ischaemic stroke 1.03, 95% CI 0.85–1.25) [24], and
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Lipids and emerging risk factors
meta-analyses of statin trials report highly significant effects in younger people (70 years) [20,25], uncertainty about the benefits of statins in otherwise healthy older people remains.
Statin effects on other clinical outcomes Although most studies focus on cardiovascular effects, statin therapy may be associated with other benefits that are potentially of importance in the elderly.
Dementia and Parkinson’s disease A number of meta-analyses of both randomized controlled trials and observational studies have addressed the role of statins in prevention or treatment of dementia (see Supplementary Digital Content 1, http://links.lww.com/HCO/A20) [26 ,27 , 28,29]. In a meta-analysis of observational studies, statin therapy was associated with reduction in risk of dementia, Alzheimer’s disease and mild cognitive impairment [28]. Among patients without cognitive impairment at baseline, long-term statin therapy was associated with a 29% relative reduction in incident dementia [29]. Similarly, a recent metaanalysis of 11 observational studies demonstrated a protective effect of statins on the risk of Parkinson’s disease (RR 0.77, 95% CI 0.64–0.92, P ¼ 0.005) [30]. Despite this, long-term statin use was not significantly associated with the risk of Parkinson’s disease (RR 0.72, 95% CI 0.45–1.13, P ¼ 0.15). Controlled clinical trials are required to further explain this association. &&
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Bone density and fracture incidence Cohort studies driven by experimental evidence suggesting statin therapy inhibits osteoclast formation and bone resorption have reported increased bone mineral density and decreased fracture risk for people using statins compared with those not using statins [odds ratio (OR) 0.77, 95% CI 0.60–1.00] [31,32]. In contrast, limited data from randomized controlled trials have suggested no effect of statins on fracture risk (OR 1.03, 95% CI 0.91–1.16) [32]. More definitive results from trials designed to evaluate statin use and fracture risk in high-risk elderly patients are needed.
Frailty, institutionalization and health service utilization Frailty, defined as an excess vulnerability to stressors with reduced ability to maintain/regain premorbid 376
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function after an insult and characterized by slowness, weakness, fatigue, weight loss and low activity, is increasingly being recognized as related to and distinct from other diseases [33]. Importantly, frailty has been independently associated with falls, hospitalization and mortality in the elderly [34]. To date, few statin trials have examined frailty or frailty-specific outcomes. Of note, the PROSPER trial reported no effect of statin therapy on daily activity levels (as quantified by the Barthel index or the Instrumental Activities of Daily Living Questionnaire) in men and women aged between 70 and 82 years [22]. A few key observational studies have also examined frailty and institutionalization in the elderly. The Women’s Health Initiative observational study reported a similar incidence of frailty in current statin users and nonusers [35], the Concord Health and Ageing in Men project reported no significant association between statin use and institutionalization [36 ], and a large administrative database review indicated no reduction in health service utilization in older patients after hospitalization for ischaemic heart disease and commencement of statin [37]. &
STATINS IN THE ELDERLY: POTENTIAL RISKS The likelihood of adverse effects of drug therapy increases in older people [38]. This may be related to changes in metabolic processes and development of concomitant diseases such as chronic kidney disease (CKD), which makes the elderly much more vulnerable to drug interactions and statin toxicity. Much of the knowledge of specific adverse effects comes from spontaneous reports or from trials in a younger age group. Supplementary Digital Content 2 (http://links.lww.com/HCO/A21) provides a summary of studies highlighted in the last 2 years as reporting on the potential adverse effects of statin therapy. As with efficacy, the adverse effect burden of statins in older individuals has not been well studied. As a result, it is not possible to know the balance of risks and benefits associated with the use of these agents in the older age group [39]. Among the elderly, the issues most likely to influence the risk/benefit balance are myopathy, diabetes, cancer and cognitive impairment.
Myopathy All statins have been reported to cause myopathy, with the severity ranging from asymptomatic increases in creatine kinase to muscle aches and weakness to fatal rhabdomyolysis [40]. The precise mechanisms are not well understood, dose-dependent and Volume 29 Number 4 July 2014
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Statins in the elderly: an answered question? Zoungas et al.
may occur even after therapy has been tolerated for up to 1 year [41]. The estimated incidence of statin myopathy in trials has ranged from 1.4 to 5% [42] with the lowest rates reported for atorvastatin at low or high dosage [43]. Older age, female sex, concomitant use of inhibitors of cytochrome P450 3A4 and hypothyroidism are recognized risk factors for the development of statin myopathy [44]. Vitamin D may also have a role in statin-induced myopathy, although this is uncertain [45].
Diabetes In a recently published meta-analysis of statin trials, statin use was associated with a 9% increased risk for incident diabetes, with little heterogeneity between trials [46]. Meta-regression indicated that the risk of developing diabetes was highest in trials with older participants but also in those with risk factors of the metabolic syndrome [46]. Given that the absolute risk of type 2 diabetes is strongly dependent on age [47], the adverse impact of statin therapy for this group may be greater. In view of these data, the Federal Drug Administration (FDA) in 2012 modified the labelling of statins to include a warning for the potential risk of increased blood sugar levels and new type 2 diabetes [48].
Cancer The PROSPER trial reported an increased risk of cancer and cancer mortality with statin therapy among men and women older than 70 years [22]. This effect was not observed by other statin trials and was incongruent with earlier in-vitro and in-vivo experiments, which suggested that statins may inhibit tumour cell growth [31]. A metaanalysis of all statin trials suggested no overall increased risk of cancer or cancer mortality over an average follow-up of 4.8 years, albeit in a mostly middle-aged population [49]. Nonetheless, more data on the effects of statin therapy on risk of cancer in elderly patients (70–82 years) are required and further follow-up studies have been called for in such patients [39]. Longer follow-up would determine whether new cancer events could occur with time. This is especially important if statin therapy is to be advocated for primary prevention.
Cognitive impairment The FDA recently reported an analysis of the US spontaneous reporting database, FDA Adverse Event Reporting System (AERS), the published medical literature (case reports and observational studies) and randomized clinical trials to evaluate the effect of statin therapy on cognition [48]. The postmarketing adverse event reports generally described ill-defined memory loss that was reversible upon
discontinuation of statin. Most reports were from individuals over the age of 50 years. Time to onset of the impairment was highly variable, ranging from 1 day to years after statin exposure. An association between cognitive impairment and a specific statin, a specific age group, a particular statin dose or concomitant medication use was not observed. Furthermore, the cognitive impairment did not appear to be associated with fixed or progressive dementia, such as Alzheimer’s disease, and was not detectable in clinical trials measuring longer-term cognitive function using combinations of neurocognitive tests such as Mini-mental state examination (MMSE), digit test and Stroop test [22,26 ,27 ]. Nonetheless, in 2012, the FDA modified the labelling of statins to include a warning for the potential risk of cognitive effects such as memory loss and confusion [48]. &&
&&
STATIN UTILIZATION Statins are one of the most frequently dispensed drugs in the United States [50]. The British Heart Foundation reported that, in 2011, one million statin prescriptions were provided each week in England [51]. At present, statin use in the elderly is lower than expected given the high absolute risk of this population. A UK survey of 41 250 GP medical records reported that 23% of patients aged 75 years or older with no history of CVD were prescribed statin therapy compared with 29% in the 70–74-year age group [52 ]. Among patients aged 75 years or older, for every 5-year increment in age, the odds of being prescribed a statin decreased compared with the 40–44-year age group. Similarly, one US study reported that 22% of people aged 80 years or older (in a primary prevention setting) were prescribed a statin [53 ] and another reported that those aged 65–69 years were more likely to use a statin than those aged 70 years or older [54 ]. &
&
&
IMPLICATIONS OF GUIDELINES FOR TREATMENT OF ELEVATED CHOLESTEROL IN THE ELDERLY The potential for greater use of statins among older people is illustrated by Fig. 3a and b. This provides an approximation of the proportion of each age group in which the absolute cardiovascular risk exceeds a 15% likelihood of a new vascular event in the next 5 years (commonly regarded as the fundamental indication for statin therapy) [55]. It is based on the cardiovascular death rate reported in the West of Scotland Coronary Prevention Study (WOSCOPS) multiplied by four, as there were four incident cardiovascular events for each fatal
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Lipids and emerging risk factors
Percentile of 10-year CHD mortality risk
(a)
Age 30–34
35–39
40–44
45–49
50–54
55–59
60–64
65–69
70–74
75–79
80–84
85+
SUM CHD deaths
2–5 6–10 11–15 16–20 21–25 26–30 31–35 36–40 41–45 46–50 41–55 56–60 61–65 66–70 71–75 76–80 81–85 86–90 91–95 96–100 SUM
0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 2 2 2 12
0 0 0 1 1 1 1 1 1 1 1 2 2 2 2 3 3 4 5 6 37
1 1 1 2 2 2 2 3 3 3 3 4 4 4 5 5 6 8 11 14 84
2 2 3 3 4 4 5 5 6 6 7 7 8 9 10 11 13 16 19 22 162
4 5 6 7 7 8 9 10 11 11 12 13 14 16 18 20 23 28 33 39 294
7 9 10 12 13 14 15 16 17 18 19 21 22 24 26 29 33 39 45 52 441
9 12 14 16 18 19 21 22 24 25 27 29 31 34 37 42 48 57 66 75 626
13 16 18 21 23 25 27 30 32 34 37 40 43 47 51 56 62 72 82 92 821
21 25 29 32 36 39 41 44 45 48 51 55 58 63 67 73 79 89 99 109 1103
38 44 50 54 57 59 62 65 68 71 75 79 84 88 94 102 111 124 141 158 1624
54 61 69 76 82 88 93 97 101 105 110 115 120 126 133 141 150 161 173 185 2240
54 64 73 83 91 98 104 109 114 119 124 129 133 139 145 153 162 174 187 199 2454
102 109 116 123 128 133 140 147 154 160 166 171 176 182 189 197 210 236 263 290 3392
305 348 389 430 462 490 520 549 576 601 632 666 696 735 778 833 901 1010 1126 1243 13290
% of all CHD deaths
0%
0%
1%
1%
2%
3%
4%
6%
8%
12%
17%
18%
26%
80–84
85+
(b)
Percentile of 10-year CHD mortality risk
% of all
25–29
2% 3% 3% 3% 3% 4% 4% 4% 4% 5% 5% 5% 5% 6% 6% 6% 7% 8% 8% 9%
Age 25–29
30–34
35–39
40–44
45–49
50–54
55–59
60–64
65–69
70–74
75–79
% of all
SUM CHD deaths
1–5
0
0
0
0
1
1
2
3
6
13
24
46
123
219
2%
6–10
0
0
0
0
1
1
2
4
8
15
28
53
150
262
2%
11–15
0
0
0
1
1
1
3
5
10
17
31
61
176
306
3%
16–20
0
0
0
1
1
2
3
5
11
20
35
69
202
349
3%
21–25
0
0
0
1
1
2
3
6
12
22
38
75
223
383
3%
26–30
0
0
0
1
1
2
4
7
13
24
42
82
239
415
4%
31–35
0
0
0
1
1
2
4
8
14
26
45
87
254
442
4%
36–40
0
0
0
1
2
3
4
8
15
28
47
91
268
467
4%
41–45
0
0
0
1
2
3
5
9
16
31
51
95
283
496
4%
46–50
0
0
0
1
2
3
5
9
16
33
55
100
301
525
4%
51–55
0
0
1
1
2
3
6
9
17
36
60
105
323
563
5%
56–60
0
0
1
1
3
4
6
10
18
37
67
112
346
605
5%
61–65
0
0
1
2
3
4
7
10
19
39
75
120
367
647
6%
66–70
0
0
1
2
3
5
7
11
21
41
84
129
382
686
6%
71–75
0
1
1
2
4
5
8
12
23
44
93
140
391
724
6%
76–80
0
1
1
2
4
6
9
14
25
49
103
152
397
763
6%
81–85
0
1
1
3
5
7
11
17
27
55
115
167
406
815
7%
86–90
0
1
2
4
6
10
14
20
33
65
134
194
430
913
8%
91–95
1
1
3
5
8
12
19
26
41
79
153
221
455
1024
9%
96–100
1
1
3
6
10
14
24
32
51
93
172
249
482
1138
10%
11742
SUM
2
6
15
36
61
90
146
225
396
767
1452
2348
6198
% of all CHD deaths
0%
0%
0%
0%
1%
1%
1%
2%
3%
7%
12%
20%
53%
FIGURE 3. The proportion of each age group in each absolute cardiovascular risk stratum for (a) males and (b) females. The shaded section under the thick black line shows the approximate percentage of each age group with a risk of 15% of developing a cardiovascular event in the next 5 years. The different shades of blue show the proportions with a 5, 10, 15 and 20% risk.
event in this study [56]. On this basis, most males over the age of 75 years, and a high percentage of females, would qualify for consideration of statin therapy. Greater use of statins is also likely to be driven by the recent change in the American College of Cardiology/American Heart Association guidelines on the treatment of cholesterol to reduce vascular events, which have caused controversy by now 378
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recommending moderate-to-high-intensity statin therapy for people aged 40–75 years at much lower absolute risk (i.e. 10-year absolute cardiovascular risk of 7.5% or higher compared with 20% or higher in previous guidelines), with no requirement for monitoring of lipid levels [57 ]. This change would appear premature in the elderly, in whom an absence of clear evidence on the benefits versus the adverse effects continues to be an issue for statin therapy, as &&
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Statins in the elderly: an answered question? Zoungas et al.
highlighted by the recent literature (Supplementary Digital Content 1 and 2).
REFERENCES AND RECOMMENDED READING
NEED FOR FURTHER RESEARCH
Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest
Given the potential for widespread use of statins amongst the elderly, more certainty about the scale of any likely benefit is needed. Although a reduced age-specific incidence of CVD, stroke and vascular dementia might well be enough to prevent frailty and delay the need for residential care, the time for a real world trial examining the impact of statin therapy has now arrived. The STAtins for Reducing Events in the Elderly (STAREE) trial will be the first randomized controlled trial of statin therapy in an apparently healthy elderly cohort living independently in the community. STAREE will determine the effects of statin therapy versus placebo on overall survival (all-cause death) or disability-free survival (need for permanent residential care) over an average 5-year treatment period amongst approximately 12 000 elderly Australians (70 years). STAREE will be conducted in Australian general practice and utilize the resources and expertise in communitybased research. This study has the potential to influence the care of elderly people in countries across the developed world and to change the way that preventive drugs are evaluated in this age group.
CONCLUSION Meta-analysis of trials highlights the uncertainty about the efficacy of statins in the prevention of morbidity and mortality in older populations. This may stem from inadequate numbers in this age group included in major trials. Warnings about adverse effects of statins have recently been added to the product information, but their frequency is uncertain, and appears higher in the elderly. Real world trials examining the impact of statin therapy in older people are now called for. STAREE will determine the effects of statin therapy versus placebo on overall survival (all-cause death) or disability-free survival (need for permanent residential care) over an average 5-year treatment period among the elderly (70 years). Acknowledgements None. Conflicts of interest S.Z. is supported by a Heart Foundation of Australia Career Development Fellowship. All authors had access to the data and played a role in writing this article. S.Z. has served on advisory boards and/or received honoraria for speaking engagements from MSD, Amgen, Astra Zeneca and BMS.
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