Abstract
Purpose
Recent epidemiological evidence has suggested that use of lipid-lowering medications, particularly statins, was associated with reduced cardiovascular disease (CVD) events and persistent physical disability in healthy older adults. However, the comparative efficacy of different statins in this group remains unclear. This study aimed to compare different forms of statins in their associations with CVD and physical disability in healthy older adults.
Methods
This post hoc analysis included data from 5981 participants aged ≥ 70 years (≥ 65 if US minorities; median age:74.0) followed for a median of 4.7 years, who had no prior CVD events or physical disability and reported using a statin at baseline. The incidence of the composite and components of major adverse cardiovascular events and persistent physical disability were compared across different statins according to their type, potency, and lipophilicity using multivariable Cox proportional-hazards models.
Results
Atorvastatin was the most used statin type at baseline (37.9%), followed by simvastatin (29.6%), rosuvastatin (25.5%), and other statins (7.0%, predominantly pravastatin). In comparisons of specific statins according to type and lipophilicity (lipophilic vs. hydrophilic statin), observed differences in all outcomes were small and not statistically significant (all p values > 0.05). High-potency statin use (atorvastatin and rosuvastatin) was marginally associated with lower risk of fatal CVD events compared with low-/moderate-potency statin use (hazard ratio: 0.59; 95% confidence interval: 0.35, 1.00).
Conclusion
There were minimal differences in CVD outcomes and no significant difference in persistent physical disability between various forms of statins in healthy older adults. Future investigations are needed to confirm our results.
Keywords: Statins, The aged, Primary prevention, Cardiovascular disease, Survival
Introduction
Statins are commonly used low-density lipoprotein cholesterol (LDL-c)–lowering agents which reduce the risk of cardiovascular disease (CVD) events [1]. However, there is a lack of consensus on the net benefit of statin therapy in individuals aged ≥ 75 years without established CVD, due primarily to the limited trial data available in this age group [2]. As age is the major determinant of risk for CVD events, it is possible that statins could benefit older adults in primary prevention settings and lower the cost for geriatric health care attributable to CVD and its sequelae [3]. Accordingly, there is a need for research which can inform whether statin prescribing for primary prevention in this age group is beneficial [4–7].
We previously investigated the associations of statin use with CVD and non-CVD outcomes in 18,096 individuals aged ≥ 70 years without prior CVD events, diagnosed dementia, or major physical disability, who were enrolled in the Aspirin in Reducing Events in the Elderly (ASPREE) randomized trial and followed for a median of 4.7 years [8]. The results showed that baseline statin use was associated with significant risk reductions in CVD events (major adverse cardiovascular events [MACE], 32%; fatal CVD, 29%; myocardial infarction [MI], 44%; stroke 25%) and persistent physical disability (25%). There was no evidence of a difference in disability-free survival, all-cause mortality, or incident dementia. Because the analysis grouped all statins together, conclusions about the potential differential effects attributable to specific statins cannot be made.
Despite the ability of all statins to reduce cholesterol, the different statins vary in their chemical structure, pharmacokinetics (lipophilicity etc.), LDL-c-lowering potency, and the potential pleiotropic effects that may result in differential within-class clinical effects [9, 10]. This may have even more relevance in older adults due to the accompanying age-related changes in pharmacokinetics and pharmacodynamics [11, 12]. Some studies have suggested that the positive associations between LDL-c and total cholesterol levels and risks of CVD and coronary heart disease events weaken with increasing age in individuals without a history of CVD [13, 14]. This means that older adults may have less to gain from using higher potency/doses of statins compared with their younger counterparts. Additionally, higher potency/doses of statin use may increase the risks for drug-related side effects and interactions to a greater extent in older adults, especially when common geriatric-related conditions such as frailty, multi-morbidity, or polypharmacy are present [15, 16]. Lipophilicity is another important consideration that may influence the risk–benefit profile of a specific statin used. Some [17–19], but not all [20, 21], studies found that hydrophilic statins were superior to lipophilic statins for reducing the risk for CVD events, although head-to-head comparative trials of hydrophilic versus lipophilic statins of equivalent potency or dose have not been undertaken. Furthermore, hydrophilic statins may cause fewer side effects and drug interactions than lipophilic statins due to a lower susceptibility to metabolism by cytochrome P450 enzymes rendering a lower risk for muscle toxicity and potentially better treatment adherence [9, 22].
Given that few studies [23–26] have directly compared the effects between different statins and that no statin trial has been completed yet in the older primary prevention population, an observational study has value to add to the evidence base regarding the comparative effects of different statin therapies in this patient group. To build upon our previous work, this follow-up analysis investigated the comparative effectiveness of statins at subclass levels using data from ASPREE participants who reported using a statin at trial entry.
Materials and methods
This post hoc analysis was exempt from ethical review as only existing de-identifiable data were used for data analyses. No new data were collected from participants for this study.
Data source and study participants
The ASPREE was a double-blind randomized placebo-controlled primary prevention trial of daily low-dose aspirin compared to placebo [27–30]. A total of 19,114 community-dwelling participants aged ≥ 70 years (aged ≥ 65 years for US minorities) with no prior CVD events, dementia, or physical disability at trial entry were recruited in Australia (87.4%) and the USA (12.6%). The trial started in January 2010 and participants were followed for a median of 4.7 years. The study design, methods, and findings of the ASPREE trial have been published elsewhere [27–30].
The present analysis included ASPREE participants who reported taking only one statin at baseline and had no missing data for baseline covariates. After excluding 13,127 participants who did not take statins at baseline, one having missing data on heart rate, and five taking two or more statins, 5981 participants were eligible for the study (Fig. 1).
Fig. 1.
Flowchart of participant selection. There were 19,114 participants initially enrolled in the ASPREE randomized trial. After the exclusion of 13,133 participants (including 13,127 non-statin users, one with missing data on heart rate, and fve using two or more statins), data from 5981 participants were used in this post hoc analysis. At baseline, atorvastatin was used most, followed by simvastatin and rosuvastatin. aOther statins included pravastatin (n = 348), fuvastatin (n = 16), lovastatin (n = 55), and pitavastatin (n = 1). bThe percentage indicates the proportion of the participants who reported use of the same statin during the follow-up as at baseline, among all baseline statin users
Assessment of statin use
Data regarding concomitant medication use (including statins and other medications) were collected from family physician records or participants’ self-report at trial entry and annual visits during follow-up. Participants were also asked to bring all current medications or a list of these to study visits to assess compliance. Statin dose was not recorded.
The types of statins used at baseline included atorvastatin, simvastatin, rosuvastatin, pravastatin, fluvastatin, lovastatin, and pitavastatin. (1) For analysis of statin type, the less commonly used statins (pravastatin, fluvastatin, lovastatin, and pitavastatin) were grouped together in an ‘other statin’ category. Atorvastatin users were treated as the reference group given its largest sample size. (2) For analyses related to potency, rosuvastatin and atorvastatin users were classified in the high-potency category and the remainder were classified into the low-/moderate-potency category (reference group), based on previous research [31, 32]. (3) For lipophilicity-level analyses, pravastatin and rosuvastatin users were classified in the hydrophilic statin category and the remainder in the lipophilic statin category, with the latter as the reference group [9].
Study outcomes
Outcome measures were major adverse cardiovascular events (MACE), MI, stroke (including both haemorrhagic and ischaemic stroke), fatal CVD, and persistent physical disability, for which lower risks were found with a statin class in our previous study [8]. MACE was a composite of any nonfatal MI, fatal/nonfatal stroke, or coronary heart disease death.
Persistent physical disability was defined as a response of ‘a lot of difficulty’, ‘unable to do activity’, or the requirement for assistance for the same basic activity of daily living (ADL) [33] at consecutive administrations of the ADL questions 6 months apart. Admission to care for assistance with daily living activities was deemed as a physical disability endpoint if the ADL questions could not be administered [29]. Except for the self-response to the ADL questions, all CVD events and admissions to care were adjudicated by Endpoint Adjudication Committees who were blinded to treatment taken.
Statistical analysis
Baseline characteristics were summarized as mean ± standard deviation (SD) for continuous variables and number with percentage for categorical variables unless indicated. Crude incidence rates for study outcomes by statin groups were calculated as the number of events divided by 1000 person/years at risk. We used Cox proportional-hazards regression models to estimate both crude and adjusted hazard ratios (HRs) for the outcomes with use of a statin according to its type, potency, and lipophilicity. The proportional-hazards assumption was checked by Schoenfeld residuals. Adjustment was made for potential baseline confounders including age, sex, race (white/non-white), country (Australia/USA), body mass index (BMI), smoking status (never, former, current), alcohol use (never, former, current), heart rate, living alone (no/yes), years of education (< 12 years/ ≥ 12 years), diabetes (none, treated, untreated), hypertension (none, treated, untreated), chronic kidney disease, family history of CVD, polypharmacy (defined as concurrent use of multiple medications [≥ 5]), and use of other lipid-lowering agents (e.g. fibrates, ezetimibe, niacin). Measurements of baseline covariates have been described elsewhere [27–30].
To make an inference concerning statin drug compliance, we also calculated and compared the LDL-c levels at baseline and at each annual follow-up visit for the entire study sample and for the different statin type subgroups.
To address the impact of in-trial statin switching, sensitivity analyses were performed in a sub-cohort (n = 5588) limited to those who reported use of the same statin during the follow-up as at baseline.
All statistical tests were 2-sided, and we considered a p value < 0.05 to be statistically significant. Analyses were performed using Stata/SE 15.0 (StataCorp, College Station, TX: StataCorp LLC).
Results
Baseline characteristics
At baseline, 2264 (37.9%) participants took atorvastatin, 1772 (29.6%) took simvastatin, 1525 (25.5%) took rosuvastatin, and 420 (7.0%) took one of the ‘other statins’ with the majority of these being on pravastatin. Participants’ median age was 74.0 years (interquartile range: 71.6 to 77.5 years) and 61.0% were women (n = 3648). The median follow-up was 4.7 years. Table 1 presents baseline characteristics of the study participants in the entire cohort and according to the type of baseline statin used.
Table 1.
Baseline characteristics of the study population
| Characteristic | Total (n = 5981) | Atorvastatin (n = 2264) | Simvastatin (n = 1772) | Rosuvastatin (n = 1525) | Other statins (n = 420) |
|---|---|---|---|---|---|
|
| |||||
| Age, years (median, IQR) | 74.0 (71.6, 77.5) | 74.2 (71.7, 77.5) | 74.4 (71.7,78.3) | 73.4 (71.5,76.5) | 74.3 (71.3, 77.8) |
| Female, n (%) | 3648 (61.0) | 1317 (58.2) | 1144 (64.6) | 917 (60.1) | 270 (64.3) |
| Race, n (%) | |||||
| White | 5672 (94.8) | 2166 (95.6) | 1650 (93.1) | 1478 (96.9) | 378 (90.0) |
| Non-white | 309 (5.2) | 98 (4.3) | 122 (6.9) | 47 (3.1) | 42 (10.0) |
| Country, n (%) | |||||
| Australia | 5155 (86.2) | 2089 (92.3) | 1375 (77.6) | 1452 (95.2) | 239 (56.9) |
| USA | 826 (13.8) | 175 (7.7) | 397 (22.4) | 73 (4.8) | 181 (43.1) |
| Smoking status, n (%) | |||||
| Never | 3262 (54.5) | 1222 (54.0) | 992 (56.0) | 814 (53.4) | 234 (55.7) |
| Former | 2481 (41.5) | 945 (41.7) | 719 (40.6) | 652 (42.8) | 165 (39.3) |
| Current | 238 (4.0) | 97 (4.3) | 61 (3.4) | 59 (3.9) | 21 (5.0) |
| Alcohol use, n (%) | |||||
| Never | 1137 (19.0) | 397 (17.5) | 365 (20.6) | 281 (18.4) | 94 (22.4) |
| Former | 379 (6.3) | 121 (5.3) | 137 (7.7) | 81 (5.3) | 40 (9.5) |
| Current | 4465 (74.7) | 1746 (77.1) | 1270 (71.7) | 1163 (76.3) | 286 (68.1) |
| BMI (kg/m2), mean ± SD | 28.9 ± 4.7 | 29.0 ± 4.7 | 28.8 ± 4.7 | 28.9 ± 4.6 | 29.1 ± 4.8 |
| Heart rate, mean ± SD | 71.0 ± 11.1 | 70.8 ± 11.1 | 70.9 ± 11.0 | 72.0 ± 11.1 | 69.6 ± 10.9 |
| Family history of CVD, n (%) | 3876 (64.8) | 1446 (63.9) | 1165 (65.8) | 1001 (65.6) | 264 (62.9) |
| Diabetes, n (%) | |||||
| None | 4782 (80.0) | 1788 (79.0) | 1428 (80.6) | 1226 (80.4) | 340 (81.0) |
| Yes (treated) | 788 (13.2) | 307 (13.6) | 232 (13.1) | 186 (12.2) | 63 (15.0) |
| Yes (untreated) | 411 (6.9) | 169 (7.5) | 112 (6.3) | 113 (7.4) | 17 (4.1) |
| Hypertension, n (%) | |||||
| None | 1062 (17.8) | 355 (15.7) | 333 (18.8) | 302 (19.8) | 72 (17.1) |
| Treated | 4076 (68.2) | 1568 (69.3) | 1206 (68.1) | 1001 (65.6) | 301 (71.7) |
| Untreated | 843 (14.1) | 341 (15.1) | 233 (13.2) | 222 (14.6) | 47 (11.2) |
| CKD, n (%) | 1733 (29.0) | 642 (28.4) | 512 (28.9) | 443 (29.1) | 136 (32.4) |
| Living alone, n (%) | 3983 (66.6) | 1544 (68.2) | 1139 (64.3) | 1043 (68.4) | 257 (61.2) |
| Education ≥ 12 years, n (%) | 3087 (51.6) | 1144 (50.5) | 952 (53.7) | 718 (47.1) | 273 (65.0) |
| Polypharmacy, n (%) | 2681 (44.8) | 1004 (44.4) | 850 (48.0) | 639 (41.9) | 188 (44.8) |
| Other lipid-lowering agents, n (%)* | 377 (6.3) | 71 (3.1) | 217 (12.3) | 72 (4.7) | 14 (4.1) |
| LDL-c, mmol/L (median, IQR) | 2.4 (2.0–1.9) | 2.4 (2.0–2.8) | 2.4 (2.0–2.9) | 2.3 (1.9–2.9) | 2.7 (2.3–3.2) |
| HDL-c, mmol/L (median, IQR) | 1.5 (1.2–1.8) | 1.5 (1.2–1.8) | 1.5 (1.3–1.8) | 1.5 (1.2–1.8) | 1.5 (1.2–1.8) |
| Total cholesterol, mmol/L (median, IQR) | 4.6 (4.1–5.2) | 4.5 (4.1–5.0) | 4.7 (4.2–5.2) | 4.6 (4.0–5.3) | 4.9 (4.4–5.4) |
Body mass index (BMI) was calculated as weight in kilogrammes divided by height in metres squared. Diabetes is defined from self-report or fasting glucose ≥ 126 mg/dl or on treatment for diabetes (treated/untreated: on/not on any glucose-lowering treatment at baseline). Hypertension is defined as ‘on-treatment’ for high blood pressure, or blood pressure ≥ 140/90 mmHg at baseline (treated/untreated: on/not on any blood pressure–lowering treatment at baseline). Chronic kidney disease (CKD) is defined as an estimated glomerular filtration rate < 60 ml/min/1.73 m2 or urinary albumin to creatinine ratio ≥ 3 mg/mmol
CVD cardiovascular disease, HDL-c high-density lipoprotein cholesterol, LDL-c low-density lipoprotein cholesterol, IQR interquartile range, SD standard deviation
Other lipid-lowering drugs refer to any non-statin lipid-lowering agent used separately from statins or as a component of acombination product for cholesterol lowering
MACE
The incidence rate of MACE among participants taking atorvastatin, simvastatin, rosuvastatin and the other statins at baseline was 7.6, 7.7, 6.6, and 11.5 cases per 1000 person/years, respectively. There was no statistically significant difference in MACE incidence between users taking different statin types (overall p = 0.48). Nor was there a difference between high-potency and low-/moderate-potency statin users (p = 0.57) and between hydrophilic and lipophilic statin users (p = 0.88) (Table 2).
Table 2.
Association between specific statin use at baseline and major adverse cardiovascular events
| Statins subclasses | N | No. of events (incidence ratea) | Unadjusted HR (95% CI) | Adjusted HRb (95% CI) | p value |
|---|---|---|---|---|---|
|
| |||||
| Type | 0.48c | ||||
| Atorvastatin | 2264 | 76 (7.6) | 1 [Ref] | 1 [Ref] | |
| Simvastatin | 1772 | 62 (7.7) | 0.99 (0.71, 1.38) | 0.98 (0.69, 1.39) | |
| Rosuvastatin | 1525 | 43 (6.6) | 0.87 (0.60, 1.26) | 0.91 (0.62, 1.33) | |
| Other statins | 420 | 22 (11.5) | 1.49 (0.93, 2.39) | 1.40 (0.84, 2.32) | |
| Potency | 0.57 | ||||
| Low/moderate | 2192 | 84 (8.4) | 1 [Ref] | 1 [Ref] | |
| High | 3789 | 119 (7.2) | 0.88 (0.66, 1.16) | 0.92 (0.68, 1.24) | |
| Solubility | 0.88 | ||||
| Lipophilic | 4108 | 142 (7.7) | 1 [Ref] | 1 [Ref] | |
| Hydrophilic | 1873 | 61 (7.5) | 0.99 (0.73, 1.34) | 1.02 (0.75, 1.39) | |
CI confidence interval
Event rate per 1000 person/years
Adjustment was made for all baseline covariates listed in Table 1
P value for overall test for pairwise comparisons of adjusted hazard ratios (HRs)
MI, stroke, and fatal CVD
The incidence rates of MI, stroke, and fatal CVD events in each statin subgroup are shown in Table 3. There was no statistically significant difference in any of these outcomes between different statin uses according to type and lipophilicity. In potency-level analyses, high-potency statin use was associated with a lower risk of fatal CVD events compared with low-/moderate-potency statin use (HR: 0.59; 95% CI: 0.35, 1.00). No other differences between high-potency and low-/moderate-potency statins were found (Table 3).
Table 3.
Association of specific statin use at baseline with myocardial infarction, stroke, and fatal cardiovascular events
| Statins subclasses | Myocardial infarction |
Stroke |
Fatal CVD |
|||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| No. of events (ratea) | Unadjusted HR (95% CI) | Adjusted HR (95%CI)b | P | No. of events (ratea) | Unadjusted HR (95% CI) | Adjusted HR (95% CI)b | P | No. of events (ratea) | Unadjusted HR (95% CI) | Adjusted HR (95% CI)b | P | |
|
| ||||||||||||
| Type | 0.08c | 0.79c | 0.1c | |||||||||
| Atorvastatin | 38 (3.8) | 1 [Ref] | 1 [Ref] | 34 (3.4) | 1 [Ref] | 1 [Ref] | 21 (2.1) | 1 [Ref] | 1 [Ref] | |||
| Simvastatin | 19(2.3) | 0.61 (0.35, 1.06) | 0.69 (0.39, 1.22) | 36 (4.5) | 1.29 (0.81, 2.06) | 1.14(0.70, 1.85) | 25 (3.1) | 1.39 (0.78, 2.49) | 1.36 (0.75, 2.48) | |||
| Rosuvastatin | 13 (2.0) | 0.52 (0.28, 0.98) | 0.56 (0.30, 1.05) | 28 (4.3) | 1.26 (0.77, 2.08) | 1.31 (0.79, 2.17) | 7(1.1) | 0.52 (0.22, 1.23) | 0.55 (0.23, 1.31) | |||
| Other statins | 10(5.2) | 1.37 (0.68, 2.75) | 1.54 (0.72, 3.29) | 9 (4.7) | 1.36 (0.65, 2.83) | 1.14(0.53, 2.46) | 7 (3.6) | 1.65 (0.70, 3.89) | 1.54 (0.63, 3.78) | |||
| Potency | ||||||||||||
| Low/moderate | 29 (2.9) | 1 [Ref] | 1 [Ref] | - | 45 (4.5) | 1 [Ref] | 1 [Ref] | - | 32 (3.2) | 1 [Ref] | 1 [Ref] | - |
| High | 51 (3.1) | 1.08 (0.68, 1.70) | 1.00 (0.62, 1.61) | 0.99 | 62 (3.8) | 0.85 (0.58, 1.24) | 0.98 (0.65, 1.48) | 0.92 | 28 (1.7) | 0.56 (0.34, 0.94) | 0.59 (0.35, 1.00) | 0.05 |
| Solubility | ||||||||||||
| Lipophilic | 58 (3.2) | 1 [Ref] | 1 [Ref] | - | 71 (3.9) | 1 [Ref] | 1 [Ref] | - | 48 (2.6) | 1 [Ref] | 1 [Ref] | - |
| Hydrophilic | 22 (2.7) | 0.87 (0.53, 1.42) | 0.86 (0.52, 1.41) | 0.54 | 36 (4.4) | 1.16 (0.78, 1.74) | 1.25 (0.83, 1.88) | 0.28 | 12(1.5) | 0.59 (0.32, 1.12) | 0.64 (0.34, 1.20) | 0.17 |
CI confidence interval, CVD cardiovascular disease
Event rate per 1000 person/years
Adjustment was made for all baseline covariates listed in Table 1
P value for overall test for pairwise comparisons of adjusted hazard ratios (HRs)
Persistent physical disability
The incidence rate of persistent physical disability among participants taking atorvastatin, simvastatin, rosuvastatin, and the other statins at baseline was 4.3, 6.4, 3.9, and 4.4 cases per 1000 person/years, respectively. There was no statistically significant difference in incidence between different statins at any subclass level (Table 4).
Table 4.
Association of specific statin use at baseline with persistent physical disability
| Statins subclasses | N | No. of events (incidence ratea) | Unadjusted HR (95% CI) | Adjusted HR (95% CI)b | p value |
|---|---|---|---|---|---|
|
| |||||
| Type | 0.42c | ||||
| Atorvastatin | 2264 | 39 (4.3) | 1 [Ref] | 1 [Ref] | |
| Simvastatin | 1772 | 47 (6.4) | 1.41 (0.92, 2.16) | 1.40 (0.90, 2.16) | |
| Rosuvastatin | 1525 | 23 (3.9) | 0.94 (0.56, 1.58) | 0.99 (0.59, 1.67) | |
| Other statins | 420 | 8 (4.4) | 0.97 (0.45, 2.07) | 1.09 (0.50, 2.37) | |
| Potency | 0.13 | ||||
| Low/moderate | 2192 | 55 (6.0) | 1 [Ref] | 1 [Ref] | |
| High | 3789 | 62 (4.2) | 0.74 (0.51, 1.06) | 0.74 (0.51, 1.09) | |
| Solubility | 0.70 | ||||
| Lipophilic | 4108 | 86 (5.2) | 1 [Ref] | 1 [Ref] | |
| Hydrophilic | 1873 | 31 (4.3) | 0.86 (0.57, 1.30) | 0.92 (0.61, 1.39) | |
CI confidence interval
Event rate per 1000 person/years
Adjustment was made for all baseline covariates listed in Table 1
P value for overall test for pairwise comparisons of adjusted hazard ratios (HRs)
LDL-c levels at baseline and each annual follow-up visit
Online Table 1 (Online Resource 1) shows LDL-c levels at baseline and each annual follow-up visit in the total study sample and in participants taking different types of statins. The very minor difference between baseline and in-trial LDL-c levels in total study sample and in each statin type group indicates a good drug compliance in each statin subgroup and in overall study sample.
Sensitivity analysis
There were 94.4% of baseline atorvastatin users, 90.9% of simvastatin users, 96.2% of rosuvastatin users, and 88.8% of the other statin users who reported use of the same statin during the follow-up as at baseline (Fig. 1). Repeating the analyses in this sub-cohort did not alter the main study findings (Online Resource 2).
Discussion
Among healthy older adults who reported statin use at trial baseline in the ASPREE trial, we found no evidence of differences in the incidences of CVD outcomes and persistent physical disability between statins according to their type, potency, and lipophilicity, except for a marginally significant reduction in risk of fatal CVD events with high-potency statin use compared with low-/moderate-potency statins. Repeating the analyses in baseline statin users who reported use of the same statin during the follow-up as at baseline did not change the conclusions drawn from the main results.
It has been suggested that evaluating the effect of statins as a class may mask potential differences in net benefits across statins with different pharmacokinetic characteristics [34]. Hence, a better understanding of the range of effects of different statins is necessary to inform appropriate statin choices that maximize the drug net benefits [35]. Built upon our previous work showing the statin-related benefits in preventing CVD events and persistent physical disability in healthy older adults, this follow-up analysis more closely examined whether the observed benefits differed across different statin uses at subclass levels [8]. Most of the results in the present study do not support the preferential prescription of a specific statin in this age group, nor do they suggest that lipophilicity is a clinically important consideration in statin selection.
An exception is that high-potency statin users were found to have a significantly lower incidence of fatal CVD events than low-/moderate-potency statin users over 4.7 years (1.7 vs. 3.2 per 1000 person/years). While it is possible that high-potency statins have a truly greater efficacy in preventing fatal CVD events than low-/moderate-potency statins, other possible explanations exist. Since high-potency statin users were slightly younger and more likely to be whites, with a lower prevalence of polypharmacy (suggesting fewer comorbidities) at baseline, they may be healthier and at less risk of fatal events including those related to CVD compared with lower potency statin users. Residual confounding may lead to an overestimated benefit of high-potency statins against fatal CVD events, despite adjustment for age, race, polypharmacy, and other CVD risk factors. In addition, an indication bias is also a likely reason for this result, as low-/moderate-potency statins are often prescribed to individuals who are more vulnerable to drug-related side effects and have an increased disease and medication burden due to frailty and other non-CVD comorbidities, which put them at a higher risk of death [36]. Beyond these possible explanations, a chance finding cannot be ruled out, since no evident impact of statin potency was found on the other CVD outcomes, including the composite of MACE.
Few studies have investigated the comparative effects of different forms of statin in older adults. In 2019, the Cholesterol Treatment Trialists’ Collaboration (CTTC) published an individual patient data meta-analysis of 28 randomized controlled trials which demonstrated a similar extent of risk reduction in major vascular events with statins/more intensive statin therapy vs. no statin/less intensive statin therapy per 1.0 mmol/L reduction in LDL-c in various age groups (≤ 55, 55–60, 60–65, 65–70, 70–75, > 75 years) among patients with vascular disease (p trend = 0.2) [2]. In contrast, there was a trend towards a smaller relative risk reduction with older age among individuals with no vascular disease (p trend = 0.05), with no evidence for significant benefit in those aged between 70 and 75 years and over 75 years. This trend with age was also found for major coronary events (p trend = 0.009) but not for stroke (p trend = 0.7) among combined groups of individuals with and without prior CVD events. Another Bayesian network analysis also found no significant differences among various types of statins for secondary prevention of CVD in older adults [37]. Similar results were seen in the analysis by Choudhry et al. of statins in 18,311 older patients with an acute coronary syndrome, and a median age of 77 years. No significant difference was found in the incidence of recurrent events between the high- and moderate-intensity statin users and between users treated with different statin types [38]. These studies suggesting similar within-class effects of statins on CVD events in the general or older secondary prevention populations are concordant with our findings in an older primary prevention population. With respect to statin characteristics, a recent meta-analysis of 11,697 participants with coronary artery disease and no age limit from 11 randomized trials showed a similar efficacy between hydrophilic and lipophilic statins in reducing the risk of MACE, MI, stroke, and fatal CVD [39]. Our study adds to these findings by showing no difference in effects on persistent physical disability between different statin forms among older adults.
Study limitations
Several limitations of this analysis merit emphasis. Firstly, this post hoc analysis used observational data and therefore statins were not randomly assigned. Therefore, we were unable to consider potential unmeasured differences in the prescribing of different statins, despite the adjustment for baseline characteristics and known risk factors. Secondly, this study did not assess the magnitude of reduction in LDL-c by each individual statin therapy due to the lack of data on participants’ pre-treatment LDL-c level. Thirdly, the doses of statins used are unknown so that we were unable to investigate any dose-dependent associations. Fourthly, the numbers of events and group sample size were relatively small in some analyses, which are likely to be underpowered. The possibility of small but clinically meaningful differences between various statins cannot be excluded. In addition, we did not assess the comparative safety between different forms of statin, which may be important when selecting an appropriate statin for older adults. Finally, the inclusion of multiple comparisons might have led to a potential increase in type I error (false positive). Given these limitations, we urge cautious interpretation of our findings.
Conclusions
Building upon our previous work suggesting the potential benefits of statins on the risk of CVD events and persistent physical disability in initially healthy older adults, this follow-up analysis found that different statins appear to be similar with respect to associations with these outcomes. Due to the observational nature of the analyses, our results should be considered hypothesis-generating only. Future studies with large sample sizes and randomization of statin type are needed to provide more definitive evidence.
Supplementary Material
Acknowledgements
The authors would like to thank the ASPirin in Reducing Events in the Elderly (ASPREE) participants who gave their precious time to participate in the ASPREE; general practitioner co-investigators; endorsing organizations; the ASPREE Investigator Group; and all members of the ASPREE team.
Funding
The ASPirin in Reducing Events in the Elderly (ASPREE) trial was supported by a grant (U01AG029824) from the National Institute on Aging and the National Cancer Institute at the National Institutes of Health, by grants (334047 and 1127060) from the National Health and Medical Research Council of Australia, and by Monash University and the Victorian Cancer Agency.
Footnotes
Conflict of interest AT reported receiving research support or honoraria from Merck, Pfizer, and Amgen, as well as Bayer for materials in the ASPREE trial and National Health and Medical Research Council (NHMRC) grant support for the Statins in Reducing Events in the Elderly (STAREE) trial. MN reported receiving a meeting honorarium from Bayer and trial product in ASPREE and NHMRC grant support for STAREE. CR reported being funded through a National Health and Medical Research Council Principal Research Fellowship. The other authors declare no competing interests.
Ethics approval This post hoc analysis was exempt from ethical review as only existing de-identifiable data were used for data analyses. No new data were collected from participants for this study.
Supplementary information The online version contains supplementary material available at https://doi.org/10.1007/s00228-021-03239-1.
Availability of data and material
Due to the nature of this research, participants of this study did not agree for their data to be shared publicly, so supporting data is not available.
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Associated Data
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Supplementary Materials
Data Availability Statement
Due to the nature of this research, participants of this study did not agree for their data to be shared publicly, so supporting data is not available.