Abstract
Background
There are no primary prevention trials of aspirin with relevant geriatric outcomes in elderly people. ASPirin in Reducing Events in the Elderly (ASPREE) is a placebo-controlled trial of low-dose aspirin that will determine whether 5 years of daily 100-mg enteric-coated aspirin extends disability-free and dementia-free life in a healthy elderly population and whether these benefits outweigh the risks.
Methods
Set in primary care, this randomized double-blind placebo-controlled trial has a composite primary endpoint of death, incident dementia or persistent physical disability. Participants aged 70+ years (non-minorities) or 65+ years (U.S. minorities) were free of cardiovascular disease, dementia, or physical disability and without a contraindication to, or indication for, aspirin. Baseline data include physical and lifestyle, personal and family medical history, hemoglobin, fasting glucose, creatinine, lipid panel, urinary albumin:creatinine ratio, cognition (3MS, HVLT-R, COWAT, SDMT), mood (CES-D-10), physical function (gait speed, grip strength), Katz activities of daily living and quality of life (SF-12).
Results
Recruitment ended in December 2014 with 16,703 Australian and 2,411 U.S. participants, a median age of 74 (range 65–98) years and 56% women. Approximately 55% of the U.S. cohort were from minority groups; 9% of the total cohort. Proportions with hypertension, overweight, and chronic kidney disease were similar to age-matched populations from both countries although lower percentages had diabetes, dyslipidemia, and osteoarthritis.
Discussion
Findings from ASPREE will be generalizable to a healthier older population in both countries and will assess whether the broad benefits of daily low-dose aspirin in prolonging independent life outweigh the risks.
Keywords: Primary prevention, Clinical trial, Dementia, Disability
Recent systematic reviews and meta-analyses of primary prevention trials have shown that aspirin reduces the relative risk of all-cause mortality and major cardiovascular events by roughly 6% and 10%, respectively (1). However, most participants in these trials were middle-aged adults with low incidence of significant adverse effects. The risk of clinically significant bleeding increases with age (2–6), and there is a paucity of clinical trials in those older than middle age; thus, the risk-to-benefit ratio of aspirin in older persons remains uncertain. Despite plausible benefits for aspirin to prevent or delay the onset of other important diseases associated with aging such as dementia, disability, cancer, and depression, no prospective intervention trials have investigated aspirin’s preventive effects for these conditions in the elderly people.
Only one clinical trial focusing on aspirin for the primary prevention of cardiovascular disease (CVD) in an older population has been reported (7). The Japanese Primary Prevention Project (JPPP) failed to show a significant benefit of open-label, low-dose aspirin on fatal and nonfatal CVD in 14,464 Japanese people aged 60 or older (including in those age-stratified to 70+ years) after an average 5 years of follow up (7). In the aspirin arm, nonfatal myocardial infarctions (hazard ratio [HR] = 0.53 [95% confidence interval 0.31–0.91]; p = .02) and transient ischemic attacks (HR = 0.57 [0.32–0.99]; p = .04) were significantly reduced, and serious extra-cranial bleeds were significantly increased (HR = 1.85 [1.22–2.81]; p = .004). As with most aspirin primary prevention studies, the JPPP was not designed to determine the balance of all the potential risks and benefits, but rather report individual groups of events, leaving open the interpretation of overall risk versus benefit of aspirin in this population.
In April 2016, the U.S. Preventive Services Task Force reported that “current evidence is insufficient to assess the balance of benefits and harms of initiating aspirin use for the primary prevention of cardiovascular disease and colorectal cancer in adults aged 70 years or older” emphasizing aspirin’s therapeutic equipoise in this age group (8). ASPirin in Reducing Events in the Elderly (ASPREE) is a multicenter, randomized, double-blinded, placebo-controlled trial of daily low-dose aspirin, conducted in the United States and Australia. It examines whether the potential benefits of 100 mg of enteric-coated aspirin daily on longevity, disability, and dementia outweigh the risks (9). As such, ASPREE is the first primary prevention aspirin study to utilize a composite primary endpoint highly relevant to elderly people, which includes dementia and persistent physical disability (surrogates of loss of independence) and all-cause mortality. The common adverse health events associated with aging that may be prevented (eg, heart disease, thromboembolism, cognitive decline, dementia, cancer, and depression) or exacerbated (eg, hemorrhagic stroke and major gastrointestinal bleeding) by aspirin all contribute to this composite endpoint, thus capturing overall benefit or harm. The composite of net effects is an outcome that matters for patients and their health care providers. Consequently, the trial findings will inform recommendations for prophylactic use of this inexpensive “over the counter” medication in the general older population.
A key question of large-scale, clinical trials such as ASPREE is its potential external validity to enable stakeholders to make recommendations and develop clinical guidelines. Although the ASPREE study is planned to conclude in 2017–2018, we describe the baseline characteristics of the 19,114 participants and compare the ASPREE cohort’s characteristics with the elderly populations from Australia and the United States for representativeness and generalizability.
Methods
The study design and sample size calculation have been previously described (9). Briefly, ASPREE participants were randomized 50:50 to 100-mg enteric-coated aspirin tablet or matching placebo after two baseline visits at which study eligibility was determined and clinical, neurocognitive, physical function, lifestyle, and other data were collected. ASPREE has multiple Institutional Review Board approvals in the United States and Australia.
Recruitment
In Australia, recruitment was mostly based in general practice (family practice) with the participant’s usual primary care (family) physician enrolled as a study coinvestigator. In the United States, recruitment was community based through academic and clinical trial centers. To achieve a goal of at least 50% minorities in the United States, the ASPREE recruitment protocol was modified in 2011 through a directive from the National Institute on Aging. Recruitment was then restricted to sites that could recruit minorities in the United States and to include minorities aged 65–69 years (African American or Hispanic). In reporting representation from minority groups, all those who self-identified as Hispanic and/or one or more of the following were included Aboriginal or Torres Strait Islander, American Indian, Asian, Black/African American, more than one race, Native Hawaiian/Other Pacific Islander/Maori, or “Other”. The category of “White” includes those who did not identify as Hispanic and identified as White/Caucasian.
Eligibility
Participants were generally healthy individuals aged 65 years and older (African American or Hispanic) or 70 years and older (all other groups). The age differential was permitted to ensure that African American and Hispanic populations could be represented in the trial, given evidence of higher burden of disease necessitating aspirin use, and their survival disadvantage (10). Interested potential community-dwelling participants were screened by phone for suitability and eligibility. After obtaining informed consent, study eligibility was determined utilizing the inclusion/exclusion criteria shown in Box 1.
Box 1. ASPREE Inclusion/Exclusion Criteria
Inclusion criteria
Able to give informed consent
Able to attend a study visit
Exclusion criteria
A past history of cardiovascular event or established CVD or atrial fibrillation
Dementia or score of <78 on Modified Mini-Mental State Examination
Disability as defined by severe difficulty or inability to perform any of the 6 Katz activities of daily living
A condition with a high current or recurrent risk of bleeding
Anemia
A condition likely to cause death within 5 years
Current use of other antiplatelet or anticoagulant medication
Current use of aspirin for secondary prevention
Uncontrolled high blood pressure (SBP ≥ 180 mmHg and/or a DBP ≥ 105 mmHg)
Randomization
Participants who met initial ASPREE eligibility criteria at a screening study visit entered a 4-week placebo run-in phase. Medication compliance was assessed at the second baseline study visit 4 weeks later. Allocation of study drug 50:50 aspirin to placebo followed a block randomization procedure and was stratified by site and age (65–79 and ≥80 years). An independent statistician using the “ralloc” procedure written for Stata (Stata Statistical Software, College Station, TX) generated the randomization list. Study participants, investigators, and general practitioner coinvestigators remain blinded to allocation of study drug.
Health Measures
Health measures were grouped as follows: physical and lifestyle measures; cardiovascular and renal biomarkers; blood pressure and heart rate; current or history of nonexclusionary morbidity; and measures of cognition, mood, physical function, and quality of life. Cognition was assessed with the Modified Mini-Mental State examination (3MS) (11), Controlled Oral Word Association Test (COWAT) (12), Hopkins Verbal Learning Test—Revised (HVLT-R) (13), and Symbol Digit Modalities Test (SDMT) (14). Depressive symptoms were assessed with the Center for Epidemiologic Studies Short Depression Scale (CES-D-10) (15). Quality of life was measured using the SF-12 reported as Mental Component Score (MCS) or Physical Component Score (PCS) (16). The eGFR values were calculated according to the CKD-EPI collaboration equation (17).
Statistical Analysis
Descriptive statistics using mean ± SD, median ± interquartile range, or number (%), as appropriate, summarized the ASPREE participants overall and divided into 65–74, 75–84, and 85+ years groups.
Results
Recruitment Statistics
Figure 1 outlines the CONSORT flowchart for ASPREE from phone screening through randomization across both countries. Phone screening was the first of four opportunities to check for eligibility and suitability for the ASPREE trial. Of the 83,376 who underwent phone screening, 72% (60,213) were ineligible or unwilling to enter a 5-year prospective drug trial.
Figure 1.
CONSORT flowchart of ASPREE participant numbers from phone screening to randomization in both countries. Visit 1 (V1) = the first face-to-face study visit for consent, checking of eligibility criteria (blood pressure, cardiovascular disease, and other clinical history, contraindication to aspirin, 3MS, Katz ADLs) and allocation of 40 days of trial medication for compliance test; Visit 2 (V2) = second face-to-face study visit with checking of eligibility criteria (hemoglobin, drug compliance >80%, general practitioner sign-off) and randomization.
Fifteen percent of those who were potentially eligible and attended the first face-to-face visit (V1) were ineligible or unwilling to proceed to the second face-to-face visit (V2). Subsequently, 3% did not progress to randomization for reasons such as low hemoglobin level, high blood pressure, or unwillingness to continue. The 19,114 randomized participants represented 23% of those originally phone screened.
Recruitment was led in Australia by the Monash University ASPREE Co-ordinating Centre (Melbourne) with regional centers located at the University of Tasmania (Hobart), the Australian National University (Canberra), and the University of Adelaide (Adelaide) (Figure 2). Fifty-one percent were living in major cities (Melbourne, Hobart, Adelaide, and Canberra) and 49% were living in regional or rural areas in four southeastern States and one Territory (Victoria, Tasmania, South Australia, New South Wales, and the Australian Capital Territory).
Figure 2.
(A) Map of Australia with rectangle of enlarged southeastern area showing the major ASPREE recruitment sites. Cities are depicted as black circles (and names) and include Melbourne VIC (6,422), Adelaide SA (1,253), Canberra ACT (1,007), and Hobart TAS (886), with recruitment numbers in parenthesis. Regional sites are depicted as numbered circles and include (with recruitment numbers in parenthesis): 1. Albury/Wodonga VIC/NSW (740); 2. Ballarat VIC (710); 3. Bendigo VIC (880); 4. Burnie TAS (664); 5. Geelong VIC (721); 6. Launceston TAS (554); 7. Mildura VIC (174); 8. Mount Gambier SA (196); 9. Sapphire Coast NSW (120); 10. Traralgon VIC (1,168); 11. Warrnambool VIC (681); 12. Wollongong NSW (527). (B) Recruitment sites in the United States are depicted as numbered circles and include 1. Birmingham AL; 2. Palo Alto CA; 3. Washington DC; 4. Gainesville FL; 5. Atlanta GA; 6. Augusta GA; 7. Chicago IL; 8. Iowa City IA; 9. Kansas City, KS; 10. Baton Rouge LA (two sites); 11. Monroe LA; 12. New Orleans LA (two sites); 13. Shreveport LA; 14. Ann Arbor MI; 15. Detroit MI (three sites); 16. Minneapolis MN; 17. St. Paul MN; 18. Greenville NC; 19. Winston-Salem NC; 20. Mineola NY; 21. Philadelphia PA; 22. Pittsburgh PA; 23. Pawtucket RI; 24. Memphis TN; 25. Dallas TX; 26. Galveston TX; 27. Harlingen TX; 28. San Antonio TX.
In the United States, recruitment and study activity were led by the Berman Center for Outcomes and Clinical Research at The Minneapolis Medical Research Foundation in Minneapolis (Minnesota). There were four major recruitment hubs, including the Berman Center, Health Partners (Minneapolis), UT Health Science Center (San Antonio), and WFU School of Medicine (Winston-Salem), which were responsible for 40 active sites recruiting across the United States.
All participants were randomized according to the ASPREE protocol inclusion and exclusion criteria, except for 38 who had protocol violations (ineligibility due to 3MS (1), Katz activities of daily living (3), high blood pressure (12), anemia (4), or clinical conditions (18)) but remained in the study.
Demographics
The median age of participants at study entry was 74 years, and the oldest participant was 98 years. Recruitment closely matched the expected age distribution (Table 1). Actual (and originally expected (9)) recruitment by age group and gender was 65–69 years 4% (0%), 70–74 years 55% (50%), 75–79 years 26% (30%), 80–84 years 11% (15%), and 85+ years 4% (5%), with 56% (55%) women. Of 1,664 minority participants, 1,323 (80%) were from the United States; minorities constituted 9% of all participants. African Americans and Hispanics comprised 85% of all minorities. The proportion of ASPREE women in the United States was higher than expected, almost double the number of men. This difference in gender representation in the United States is contributed to from both minority (39%:61%) and white (31%:69%) participants. The proportion of participants with less than 12 years of education was substantially different between the United States and Australia, with 10% in the United States and 50% in Australia (Table 1).
Table 1.
ASPREE Participants by Age, Education, Ethnicity, and Country
| All | Australia | United States | Minoritya | |
|---|---|---|---|---|
| N | 19,114 (100%) | 16,703 (87%) | 2,411 (13%) | 1,664 (9%) |
| Age (y) | ||||
| 65–74 | 11,163 (58%) | 9,668 (58%) | 1,495 (62%) | 1,218 (74%) |
| 75–84 | 7,219 (38%) | 6,395 (38%) | 824 (34%) | 385 (23%) |
| 85+ | 732 (4%) | 640 (4%) | 92 (4%) | 43 (3%) |
| Gender | ||||
| Male | 8,332 (44%) | 7,523 (45%) | 809 (34%) | 640 (39%) |
| Female | 10,782 (56%) | 9,180 (55%) | 1,602 (66%) | 1,006 (61%) |
| Education (y) | ||||
| <12 | 8,636 (45%) | 8,399 (50%) | 237 (10%) | 334 (20%) |
| ≥12 | 10,477 (55%) | 8,303 (50%) | 2,174 (90%) | 1,312 (80%) |
| Ethnicity / race | ||||
| White | 17,450 (91%) | 16,362 (98%) | 1,088 (45%) | — |
| African American | 901 (5%) | 4 (0%) | 897 (37%) | 901 (55%) |
| Hispanic | 488 (3%) | 115 (1%) | 373 (15%) | 488 (30%) |
| Asian | 164 (1%) | 128 (1%) | 36 (1%) | 164 (10%) |
| Other | 111 (1%) | 94 (1%) | 17 (1%) | 111 (7%) |
Note: Headers show the numbers (N) by country and minority (non-white) status. Row values are numbers and % of total in that category within the column.
aMinority status is defined in Methods except that any category with less than 100 participants is included under “Other” which includes Aboriginal/Torres Strait Islanders (12), American Indians (6), More than one race (64), Native Hawaiian / Pacific Islander (11) and those who were not Hispanic but reported as “Other” or “Not reported” whose minority status could not be determined (18).
With each 10 years of age (Table 2), height was lower by ~2 cm and body weight by 3–5 kg. The mean body mass index (28.1 kg/m2) was midway in the WHO standard overweight category of 25–30 kg/m2 and lower by ~1 kg/m2 for each additional 10 years. The proportion of all participants who were obese at 65–74 years (32%) dropped to 17% at age 85+ years. Current smokers constitute a small percentage (4% on average) of participants, whereas the proportion who identify as current alcohol consumers (self report) was more than 70% across all ages. In general, the level of education was high with more than 50% having 12 or more years of education. The proportion of participants living alone increased with age, with the proportion twice as high for 85+ years (58%) than 65–69 years (28%).
Table 2.
Physical and Lifestyle Measures by Age
| Age Range (y) | ||||
|---|---|---|---|---|
| 65–74 | 75–84 | 85+ | Overall | |
| N = 11,163 | N = 7,219 | N = 732 | N = 19,114 | |
| Height (m) | 1.66 (0.09) | 1.64 (0.09) | 1.62 (0.09) | 1.65 (0.09) |
| Weight (kg) | 78.8 (15.2) | 75.0 (14.4) | 69.4 (12.6) | 77.0 (15.0) |
| Waist circumference (cm; N = 18,921) | 97.6 (13.0) | 96.6 (12.8) | 94.4 (11.9) | 97.1 (12.9) |
| BMI (kg/m2) | 28.4 (4.8) | 27.8 (4.6) | 26.4 (4.1) | 28.1 (4.7) |
| BMI categories | ||||
| Underweight, <20 | 185 (2%) | 141 (2%) | 26 (4%) | 352 (2%) |
| Normal, 20–24.9 | 2,423 (22%) | 1,839 (26%) | 264 (36%) | 4,526 (24%) |
| Overweight, 25–29.9 | 4,902 (44%) | 3,264 (45%) | 314 (43%) | 8,480 (45%) |
| Obese, ≥30 | 3,610 (32%) | 1,944 (27%) | 123 (17%) | 5,677 (30%) |
| Current smoker | 514 (5%) | 205 (3%) | 16 (2%) | 735 (4%) |
| Current alcohol consumption | 8,725 (78%) | 5,386 (75%) | 530 (72%) | 14,641 (77%) |
| Education (y) | ||||
| <12 | 4,817 (43%) | 3,441 (48%) | 378 (52%) | 8,636 (45%) |
| 12–15 | 3,286 (29%) | 2,076 (29%) | 212 (29%) | 5,574 (29%) |
| 16+ | 3,060 (27%) | 1,701 (24%) | 142 (19%) | 4,903 (26%) |
| Living alone | 3,085 (28%) | 2,739 (38%) | 428 (58%) | 6,252 (33%) |
Note: Values are mean (SD) or number (%). Participant numbers (N) in each variable category are more than 19,000 unless otherwise stated.
Clinical Measures, Biomarkers, and Morbidity
Low hemoglobin level was an exclusion criterion for safety concerns. The mean ± SD hemoglobin level across all ages was 14.2 ± 1.2 g/dL, falling approximately 0.2 g/dL with each decade (Table 3). Levels of fasting blood glucose, high density lipoprotein, and total cholesterol differed little with age. Renal function was lower in older age; eGFR was lower by 12.6 mL/min/1.73 m2 in those aged 85+ years (43% with eGFR < 60 mL/min/1.73 m2) compared with the 65- to 74-year age group (11% with eGFR < 60 mL/min/1.73 m2). Diabetes was present in 11% of participants, consistent across the age groups, with a population fasting glucose of 99 ± 19 mg/dL.
Table 3.
Clinical Measures at Baseline by Age Group
| 65–74 Years | 75–84 Years | 85+ Years | Overall | |
|---|---|---|---|---|
| Hemoglobin (g/dL) | 14.3 (1.2) | 14.1 (1.2) | 13.8 (1.2) | 14.2 (1.2) |
| Fasting glucose (mg/dL; N = 18,775) | 99.0 (19.6) | 98.5 (18.2) | 98.0 (18.3) | 98.8 (19.0) |
| HDL (mg/dL; N = 18,675) | 61.1 (18.6) | 61.8 (18.2) | 64.0 (18.2) | 61.5 (18.5) |
| Total cholesterol (mg/dL; N = 18,929) | 203.5 (38.3) | 201.6 (38.0) | 200.5 (39.5) | 202.7 (38.2) |
| Serum/plasma creatinine (mg/dL; N = 18,647) | 0.9 (0.2) | 0.9 (0.2) | 1.0 (0.3) | 0.9 (0.2) |
| eGFR (mL/min/1.73 m2; N = 18,451) | 75.6 (13.7) | 69.9 (13.9) | 62.9 (14.1) | 73.0 (14.2) |
| SBP (mmHg) | 138.1 (16.2) | 140.4 (16.7) | 143.6 (17.2) | 139.2 (16.5) |
| SBP ≥ 160 mmHg | 1,173 (11%) | 991 (14%) | 143 (20%) | 2,307 (12%) |
| DBP (mmHg) | 78.1 (9.8) | 76.2 (10.1) | 74.8 (10.6) | 77.3 (10.0) |
| DBP ≥ 90 mmHg | 1,407 (13%) | 730 (10%) | 67 (9%) | 2,204 (12%) |
| Heart rate (bpm) | 70.7 (10.6) | 70.7 (10.8) | 71.4 (11.6) | 70.7 (10.7) |
| Diabetes mellitusa | 1,187 (11%) | 788 (11%) | 83 (11%) | 2,058 (11%) |
| Hypertension | 8,022 (72%) | 5,564 (77%) | 609 (83%) | 1,4195 (74%) |
| Personal cancer historya | 2,009 (18%) | 1,467 (20%) | 183 (25%) | 3,659 (19%) |
| eGFR < 60 mL/min | 1,494 (11%) | 1,624 (23%) | 301 (43%) | 3,419 (19%) |
| Osteoarthritisa (N = 5,677) | 1,177 (33%) | 771 (40%) | 83 (42%) | 2,031 (36%) |
| Concomitant medication usea | 9,525 (85%) | 6,453 (89%) | 661 (90%) | 16,639 (87%) |
| Statin usea | 3,794 (34%) | 2,476 (34%) | 200 (27%) | 6,470 (34%) |
| Previous regular aspirin usea | 1,145 (10%) | 844 (12%) | 105 (14%) | 2,094 (11%) |
| CES-D-10 score 8+ | 1,077 (10%) | 724 (10%) | 78 (11%) | 1,879(10%) |
Notes: CES-D-10 = Center for Epidemiologic Studies Short Depression Scale; DBP = diastolic blood pressure; eGFR = estimated glomerular filtration rate (17); HDL = high density lipoprotein; SBP = systolic blood pressure.
Values are mean (SD) or number (%). Participant numbers (N) in each variable category are more than 19,000 unless otherwise stated. A specific question about osteoarthritis was asked after June 2013, hence the low “N.” BPs were the average of three readings taken with an automated monitor, 1 minute between readings. Concomitant medication use refers to one or more prescription medications, not including study medication. Statin use = any statin. Heart rate is the average of three readings.
Definitions of morbidity: Diabetes mellitus = self-report of diabetes or fasting glucose ≥ 126 mg/dL or on treatment for diabetes; Hypertension = SBP ≥ 140 mmHg or DBP ≥ 90 mmHg or on treatment for high blood pressure.
aSelf report.
Overall, mean ± SD SBP of ASPREE participants was 139 ± 17 mmHg and DBP was 77 ± 10 mmHg. As the age of participants increased from 65–74 to 85+ years, SBP rose by 5.5 mmHg and DBP fell by 3.3 mmHg. At randomization, 12% of all participants had SBP ≥ 160 mmHg or DBP ≥ 90 mmHg. When drug treatments for high blood pressure were included in the definition of hypertension, 74% of all participants had hypertension, with the proportion increasing with age (72% in 65–74 year olds to 83% in 85+ year olds). The heart rate of ASPREE participants of 71 ± 11 beats per minute varied little across age groups.
Nineteen percent of participants reported a personal history of cancer, with the percentage increasing from 18% in those aged 65–74 years to 25% in those aged 85+ years. Osteoarthritis was present in 36% of participants in whom a specific question about osteoarthritis was administered (n = 5,677, for explanation see Table 3 footnote), increasing from 33% in the youngest to 42% of those 85+ years. Seven percent of participants had a screening cutoff of ≥8 for depression on the CES-D-10 scale with little difference by age group. Overall, 87% of ASPREE participants were taking at least one prescription medication and 34% were taking a statin. Eleven percent of participants identified as having been regular aspirin users prior to enrolling in ASPREE.
Neurocognitive, Mood, Physical Function, and Quality of Life Measures
The mean age at enrolment was 75.1 years and the mean ± SD years of education were 12.6 ± 3.7 (Table 4). The mean ± SD of 3MS was 93.4 ± 4.6. SDMT scores were broadly comparable in ASPREE participants with the performance of similarly aged and educated elderly Australians (18). The overall HVLT-R delayed recall score in ASPREE participants of 7.7 ± 2.8 compares closely with published normative data of 7.8 ± 2.7 from 394 community-dwelling elderly persons who had a higher mean level of education (14.1 years) and age range of 60–84 years (19). For the COWAT, most studies report the total score of words from three different designated letters, including “F+A+S” or “C+F+L”. Verbal fluency was assessed in ASPREE participants with only one trial of words beginning with the letter “F”. Mean COWAT score of 12.1 ± 4.6 in ASPREE participants was comparable with older Australians of similar age and level of education (20).
Table 4.
Cognitive, Mood, Physical Function, and Quality of Life Measures by Age Group
| 65–74 | 75–84 | 85+ | Overall | |
|---|---|---|---|---|
| Years of education | 12.8 (3.7) | 12.4 (3.6) | 12.0 (2.5) | 12.6 (3.7) |
| 3MS | 93.9 (4.4) | 92.9 (4.8) | 91.3 (5.2) | 93.4 (4.6) |
| HVLT-R (Delayed recall) | 8.1 (2.7) | 7.3 (2.9) | 6.3 (2.9) | 7.7 (2.8) |
| COWAT | 12.2 (4.6) | 11.9 (4.6) | 11.9 (4.6) | 12.1 (4.6) |
| SDMT | 38.7 (9.8) | 34.5 (9.9) | 29.1 (9.9) | 36.7 (10.2) |
| CES-D-10 score; median (IQR) | 2 (1–5) | 2 (1–5) | 2 (1–5) | 2 (1–5) |
| Gait time to walk 3 m (s) | 3.0 (0.9) | 3.3 (0.9) | 3.9 (1.2) | 3.2 (1.0) |
| Grip strength, dominant hand (kg; N = 18,835) | 28.5 (10.2) | 24.9 (9.3) | 21.0 (8.4) | 26.9 (10.0) |
| No difficulty—one flight of stairs | 9,802 (88%) | 5,925 (82%) | 539 (74%) | 16,266 (85%) |
| SF-12 MCS | 55.6 (7.1) | 55.7 (7.2) | 55.9 (7.5) | 55.7 (7.1) |
| SF-12 PCS | 49.2 (8.5) | 47.4 (8.9) | 44.2 (9.2) | 48.3 (8.8) |
Notes: 3MS = Modified Mini-Mental State examination; COWAT = Controlled Oral Word Association Test; HVLT-R = Hopkins Verbal Learning Test—Revised; IQR = interquartile range; MCS = Mental Component Score, PCS = Physical Component Score from the SF-12; SDMT = Symbol Digit Modalities Test.
Participant numbers (N) in each variable category are more than 19,000 unless otherwise stated. Values are mean (SD), number (%) or median (IQR). Gait time over 3 m was the average of two trials per person (participants were asked to walk at “your usual speed as if you were walking down the street to go to the store”), individual hand grip strength was the mean of three trials of the dominant hand.
Grip strength was lower on average by 7.5 kg in those aged 85+ years compared with those aged 65–74 years. Time to walk 3 m (gait speed) was longer with older age, with means of 3.0 and 3.9 seconds for those aged 65–74 years and 85+ years, respectively. Most participants (85%) had no difficulty climbing a flight of stairs at study entry although this proportion was only 74% in the 85+ years.
Mean scores on the two derived mental and physical components (MCS and PCS) of the SF-12 quality of life instrument were mean ± SD of 55.7 ± 7.1 and 48.3 ± 8.8, respectively, across all participants. The mean MCS for ASPREE participants aged 65–74 years was 2 to 4 points higher than equivalent population data in both countries and the mean PCS was 4 points higher than population data for 65–74 years from both countries (21,22). MCS did not vary with age whereas PCS was lower in older age group, similar to other reports (21,22).
Comparisons With Country-Specific Population Data
More than 60% of the Australian ASPREE participants were located in the State of Victoria at study enrolment, so health risk data of Australian participants were compared with Victorian State Government statistics (Table 5) (23). In the United States, the comparator data were derived primarily from CDC Health, United States, 2015 Trend Tables for those aged 65+ years in 2010–2014 (24–26). Australian ASPREE participants had less diabetes (by 5%) and osteoarthritis (by 18%) although a higher proportion had hypertension (by 11%). In the United States, the ASPREE participants also had less diabetes (by 9%) and osteoarthritis (by 17%), and a similar proportion with hypertension. A similar proportion of ASPREE participants in both countries had chronic kidney disease.
Table 5.
Morbidity and Health Risks in ASPREE Participants Compared With Country-Specific Population Data
| Australia | United States | |||
|---|---|---|---|---|
| ASPREE Participants (%) | General Population (%) | ASPREE Participants (%) | General Population (%) | |
| Diabetes mellitus | 10 | 15 | 17 | 26 |
| Hypertension | 75 | 64 | 69 | 71 |
| Osteoarthritis | 36 | 54 | 33 | 50 |
| CKD (eGFR < 60 mL/min/1.73 m2) | 18 | 19 | 20 | 23 |
| BMI 25–29.9 kg/m2 | 45 | 45 | 40 | 35 |
| BMI ≥ 30 kg/m2 | 29 | 33 | 35 | 38 |
| Dyslipidemiaa | 68 | 79 | 47 | 57 |
| Smoking (current)b | 3 | 8 | 7 | 9 |
| Health ratingc (fair/poor) | 4 | 11 | 7 | 25 |
Note: Definitions as described for Table 3.
aDyslipidemia includes those taking cholesterol-lowering medications or serum cholesterol ≥212 mg/dL (Australia) and ≥240 mg/dL (United States) with these cutoffs aligning with the definitions used in available country-specific comparative data (23–26). bSmoking = current smoker. cHealth rating = self-reported health rating of fair/poor on the SF-12 (9,10).
The proportions of ASPREE participants who were overweight (25–29.9 kg/m2) or obese (≥30 kg/m2) were similar to the general populations of both countries. Compared with country-specific population data, a smaller proportion of ASPREE participants had dyslipidemia (combination of high cholesterol or taking lipid-lowering medication). A smaller proportion of ASPREE participants, from both countries, rated their health as fair or poor compared with the general population in each country, and there were proportionately fewer smokers in ASPREE.
Discussion
This article reports the successful recruitment across two countries of more than 19,000 older persons into a primary prevention trial of low-dose aspirin. Recruitment locations included major cities and metropolitan areas, large and small regional towns, and more remote rural areas. The baseline characteristics of this large healthy aging trial population are generally representative of its source populations. ASPREE participants were recruited between March 2010 and December 2014, with specific recruitment strategies to enable representation of U.S. minority groups. The recruitment strategy resulted in efficiency in retention of interested people after the initial face-to-face baseline visit 1—there was a loss of 10% from baseline visit 1 to baseline visit 2 and of 4% from baseline visit 2 to randomization. Participants exhibit a healthy survivor bias as they have successfully made it through middle age without a clinical indication for use of regular aspirin. Many participants would have previously used aspirin (11% had regular use) on an intermittent basis due to the over-the-counter status of aspirin for common minor ailments (27). This familiarity may go some way to explain the high study recruitment.
Study recruitment closely matched the expected age distribution, which is important for anticipated rates of primary and secondary endpoint events and hence feasibility. Just under half the participants (42%) were 75 years or older, including 4% older than 85 years. ASPREE participants include 9% minorities, defined here as non-White population, which is comparable with the 10% of the general U.S. population in 2010 who were older than 65 years and non-White/Caucasian (28).
The proportion of ASPREE participants with osteoarthritis (36%), increasing with age, is lower than in the general population. There was a high burden of hypertension (74%) in the ASPREE cohort, increasing with age, but broadly in line with general population trends from both countries. Older age in ASPREE is also associated with lower gait speed and handgrip strength, indicating increasing frailty. This is supported by the reduction in the physical component score derived from the SF-12 observed with age.
One in five ASPREE participants is a cancer survivor, reflecting both its prevalence associated with aging, and higher survival rates. Older age groups had a higher probability of living alone, likely the result of spousal death. The MCS derived from the SF-12 and the screen for depression with the CES-D-10 did not show marked differences with age in mental health or mood of ASPREE participants.
Overall, these demographic characteristic findings indicate that the ASPREE participants are somewhat healthier than the general population of similar age, as would be expected from a “healthy aging” study, but nevertheless are broadly representative of the community-dwelling older population in both countries.
Conclusion
ASPREE represents the first primary prevention trial of low-dose aspirin in healthy elderly people to determine its effect in preventing a composite geriatric endpoint including dementia, physical disability, or death, rather than a singular cardiovascular endpoint. The cohort characteristics suggest strong external validity for generalizing the results from ASPREE to the healthy elderly population in both countries. As such, it will determine whether an inexpensive common medication can prevent the most significant outcomes of aging, and in so doing promote prolongation of healthy independent life.
Funding
The work was supported by the National Institute on Aging and the National Cancer Institute at the National Institutes of Health (grant number U01AG029824); the National Health and Medical Research Council of Australia (grant numbers 334047 and 1127060); Monash University (Australia); the Victorian Cancer Agency (Australia).
Acknowledgments
A. G. Bayer provided aspirin and matching placebo. The authors acknowledge the dedicated and skilled staff in Australia and the Unites States for the conduct of the trial. The authors also are most grateful to the ASPREE participants, who so willingly volunteered for this study, and the general practitioners and medical clinics who support the participants in the ASPREE study.
Trial Registration: International Standard Randomized Controlled Trial Number Register (ISRCTN83772183) and clinicaltrials.gov (NCT01038583).
References
- 1. Sutcliffe P, Connock M, Gurung T, et al. Aspirin for prophylactic use in the primary prevention of cardiovascular disease and cancer: a systematic review and overview of reviews. Health Technol Assess. 2013;17:1–253. doi:10.3310/hta17430 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Hernández-Díaz S, Rodríguez LA. Association between nonsteroidal anti-inflammatory drugs and upper gastrointestinal tract bleeding/perforation: an overview of epidemiologic studies published in the 1990s. Arch Intern Med. 2000;160:2093–2099. doi:10.1001/archinte.160.14.2093 [DOI] [PubMed] [Google Scholar]
- 3. He J, Whelton PK, Vu B, Klag MJ. Aspirin and risk of hemorrhagic stroke: a meta-analysis of randomized controlled trials. JAMA. 1998;280:1930–1935. doi:10.1001/jama.280.22.1930 [DOI] [PubMed] [Google Scholar]
- 4. Hernández-Díaz S, Rodríguez LAG. Incidence of serious upper gastrointestinal bleeding/perforation in the general population. J Clin Epidemiol. 2002;55:157–63. doi:10.1016/S0895-4356(01)00461-9 [DOI] [PubMed] [Google Scholar]
- 5. de Rooij NK, Linn FH, van der Plas JA, Algra A, Rinkel GJ. Incidence of subarachnoid haemorrhage: a systematic review with emphasis on region, age, gender and time trends. J Neurol Neurosurg Psychiatry. 2007;78:1365–1372. doi:10.1136/jnnp.2007.117655 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. van Asch CJ, Luitse MJ, Rinkel GJ, van der Tweel I, Algra A, Klijn CJ. Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis. Lancet Neurol. 2010;9:167–176. doi:10.1016/S1474-4422(09)70340-0 [DOI] [PubMed] [Google Scholar]
- 7. Ikeda Y, Shimada K, Teramoto T, et al. Low-dose aspirin for primary prevention of cardiovascular events in Japanese patients 60 years or older with atherosclerotic risk factors: a randomized clinical trial. JAMA. 2014;312:2510–2520. doi:10.1001/jama.2014.15690 [DOI] [PubMed] [Google Scholar]
- 8. Bibbins-Domingo K. Aspirin use for the primary prevention of cardiovascular disease and colorectal cancer: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2016;164:836–845. doi:10.7326/M16-0577 [DOI] [PubMed] [Google Scholar]
- 9. ASPREE Investigator Group. Study design of ASPirin in Reducing Events in the Elderly (ASPREE): a randomized, controlled trial. Contemp Clin Trials. 2013;36:555–564. doi:10.1016/j.cct.2013.09.014 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. National Center for Health Statistics. National Center for Health Statistics, United States, 2011 with Special Feature on Socioeconomic Status and Health http://www.cdc.gov/nchs/data/hus/hus11.pdf [PubMed]
- 11. Teng EL, Chui HC. The Modified Mini-Mental State (3MS) examination. J Clin Psychiatry. 1987;48:314–318. doi:10.3310/hta17430 [PubMed] [Google Scholar]
- 12. Ross TP. The reliability of cluster and switch scores for the Controlled Oral Word Association Test. Arch Clin Neuropsychol. 2003;18:153–164. doi:10.1093/arclin/18.2.153 [PubMed] [Google Scholar]
- 13. Brandt J, Benedict RHB.Hopkins Verbal Learning Test revised. Professional manual.Lutz, FL: Psychological Assessment Resources; 2001. [Google Scholar]
- 14. Smith A. Symbol Digits Modalities Test. Los Angeles, CA: Western Psychological Services; 1982. [Google Scholar]
- 15. Radloff LS. The CES-D Scale: a self-report depression scale for research in the general population. Appl Psychol Meas. 1977;1:385–401. doi:10.1177/014662167700100306 [Google Scholar]
- 16. Ware J, Jr, Kosinski M, Keller SD. A 12-Item Short-Form Health Survey: construction of scales and preliminary tests of reliability and validity. Med Care. 1996;34:220–233. doi:10.1097/00005650-199603000-00003 [DOI] [PubMed] [Google Scholar]
- 17. Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150:604–612. doi:10.7326/0003-4819-150-9-200905050-00006 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Kiely KM, Butterworth P, Watson N, Wooden M. The Symbol Digit Modalities Test: Normative data from a large nationally representative sample of Australians. Arch Clin Neuropsychol. 2014;29:767–775. doi:10.1093/arclin/acu055 [DOI] [PubMed] [Google Scholar]
- 19. Vanderploeg RD, Schinka JA, Jones T, Small BJ, Graves AB, Mortimer JA. Elderly norms for the Hopkins Verbal Learning Test-Revised. Clin Neuropsychol. 2000;14:318–324. doi:10.1076/1385-4046(200008)14:3;1-P;FT318 [DOI] [PubMed] [Google Scholar]
- 20. Wardill T, Anderson V, Graham A, Perre D. Normative Data for Older Australians (Chapter 8). Melbourne, Australia: Melbourne Neuropsychology Services; 2009:8.1–8.6. [Google Scholar]
- 21. Ware JE, Kosinski N, Turner-Bowker DM, Gandek B. How to Score Version 2 of the SF-12 Health Survey (with a supplement documenting version 1). Lincoln, RI: QualityMetric; 2002. [Google Scholar]
- 22. Avery J, Dal Grande E, Taylor A. Quality of Life in South Australia as Measured by the SF12 Health Status Questionnaire. South Australia: Population Research and Outcome Studies Unit, Department of Human Services. [Google Scholar]
- 23. Department of Health, Melbourne. The Victorian Health Monitor: Prevention and Population Health Branch, Victorian Government Department of Health, Melbourne, Victoria 2012 http://www.health.vic.gov.au/healthstatus/survey/vhm.htm
- 24. National Center for Health Statistics, U.S. Department of Health and Human Services. Health, United States, 2015 With Special Feature on Racial and Ethnic Health Disparities. Hyattsville, MD: U.S. Department of Health and Human Services; 2015. [PubMed] [Google Scholar]
- 25. Centers for Disease Control and Prevention. Prevalence of Doctor-Diagnosed Arthritis and Arthritis-Attributable Activity Limitation—United States, 2010–2012. Morbidity and Mortality Weekly Report, U.S. Department of Health and Human Services. Atlanta, GA: Centers for Disease Control and Prevention; 2013. [Google Scholar]
- 26. United States Renal Data System Annual Data Report 2015. Epidemiology of Kidney Disease in the United States. In: National Institutes of Health, ed. Bethesda, MD: USRDS United States Renal Data System; 2015. [Google Scholar]
- 27. Roth GA, Gillespie CW, Mokdad AA, et al. Aspirin use and knowledge in the community: a population- and health facility based survey for measuring local health system performance. BMC Cardiovasc Disord. 2014;14:1–7. doi:10.1186/1471-2261-14-16 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28. Vincent GK, Velkoff VA.The Next Four Decades. The Older Population in the United States: 2010 to 2050. In: Department of Commerce. Economics and Statistics Administration, ed. Washington, DC: U.S. Census Bureau; 2010:P25–P1138. [Google Scholar]