The ASPREE Aftermath: A Geriatric Perspective on the Role of Aspirin in Older Adults
Despite key differences from younger populations, older adults have historically been excluded from cardiovascular trials.1-3 While older individuals are at higher risk for cardiovascular events, they are also at higher risk for adverse effects from therapies due to polypharmacy, comorbid conditions and the physiologic effects of aging. This has led many to advocate for greater inclusion of older adults in randomized trials and the NIH's soon to be effective Inclusion Across the Lifespan policy.4,5 A balanced emphasis between prolonging life and emphasizing quality of life is central to pursuing a personalized model of care.6 As a reflection of this approach, many have advocated for an increased emphasis on functional capacity as a clinical marker of health and key outcome for future clinical studies.7 This paradigm shift toward a more patient-centered model refocused on functional outcomes gained further momentum with the recent Aspirin in Reducing Events in the Elderly (ASPREE) trial,8 a randomized trial investigating aspirin versus placebo in older adults.
The ASPREE investigators enrolled 19,114 subjects 70 years and older (or ≥65 years old among black and Hispanic individuals in the US) without pre-existing cardiovascular disease, dementia or physical disability and randomized these patients to oral enteric-coated aspirin 100 mg daily versus placebo. Importantly, the primary endpoint was disability-free survival, defined as survival free from persistent disability and dementia (the first occurrence of any one of the three components: all-cause death, persistent disability or dementia). The diagnosis of dementia was based on adjudication of all participants with a clinical diagnosis of dementia, a prescription for a cholinesterase inhibitor or a significant decrease in their sequential mini-mental exams at 1, 3, 5 or 7 years or close-out. Persistent disability was defined as persistent severe difficulty or inability to complete one or more Katz activities of daily living (ADLs) for 6 or more months after incident date or adjudicated admission to a nursing facility for physical disability.
After a median of 4.7 years, the primary endpoint occurred in 9.6% of the study population, with 911 deaths (50% of primary endpoint events), 549 dementia diagnoses (30%) and 375 participants with persistent physical disability (20%). There was no significant difference in these overall rates among those treated with aspirin or placebo (21.5 events per 1000 person-years vs. 21.2 per 1000 person-years (HR 1.01; CI: 0.92-1.11; p = 0.79). The rates of the individual components of dementia and persistent physical disability also did not differ by treatment. Unexpectedly, aspirin users in ASPREE experienced higher all-cause mortality (5.9% vs 5.2%; HR 1.14; CI 1.01-1.29)(8). This was partially driven by higher cancer-related death among those on aspirin (3.1% vs. 2.3%; HR 1.31; CI 1.10-1.56), especially cancer-related death due to colorectal cancer (0.37% vs. 0.21%, HR 1.77; CI 1.02-3.06) and more bleeding events (3.8% vs. 2.8%; HR 1.38, CI 1.18-1.62; p < 0.001). Interestingly, cardiovascular event rates did not differ significantly among those on aspirin vs placebo (3.5% vs. 3.9% HR 0.95 ; CI 0.83-1.08).9
The results of ASPREE should challenge clinicians to rethink the routine use of aspirin for primary prevention of cardiovascular events in older individuals. Overall the strategy did not reduce cardiovascular events yet it increased major bleeding events and all-cause and cancer related deaths. Why do these results differ from previous primary prevention trials with aspirin? While the original primary prevention trials using aspirin therapy demonstrated a lower risk of cardiovascular events,10-13 more recent trials including ASCEND (A Study of Cardiovascular Events iN Diabetes) in diabetic patients,14 ARRIVE (A Study to Assess the Efficacy and Safety of Enteric-Coated Acetylsalicylic Acid in Patients at Moderate Risk of Cardiovascular Disease) in moderate risk individuals,15 and now ASPREE in older adults have shown minimal or no benefit with aspirin therapy. This may be partly due to improved risk reduction strategies in all patients in contemporary practice, including more potent pharmacologic options and emphasis on healthy lifestyle changes. Older patients in ASPREE, with better lifetime risk factor control, have a lower likelihood of reducing their already low risk of thrombotic events than the trial participants from the 1980s.
The increased risk of cancer-related death seen in ASPREE runs counter to prior studies demonstrating the protective effect of aspirin for cancer-related death.16,17 It is unclear whether this finding stems from increased case ascertainment (i.e., diagnosis of otherwise clinically silent GI cancers due to bleeding on aspirin) leading to potentially toxic therapies, an unknown causal pathophysiologic mechanism or chance alone. Considering the conflicting data, we must interpret the observed increase in cancer-related death in ASPREE with caution. While the absolute observed difference was small (~1.0%), the increased risk of major bleeding seen in ASPREE remains concerning. Bleeding is an important consideration in older adult populations who experience significant morbidity and mortality from bleeding events. Without any meaningful observed benefit of aspirin therapy, even a small bleeding risk gives us pause.
Also, in line with the well-established relationship between frailty and cardiovascular disease in elderly patients,18-21 the ASPREE investigators conducted a pre-specified sub-group analysis of patients stratified by frailty status (not frail, pre-frail, frail). There was a trend toward improved disability free survival with aspirin in pre-frail patients (HR 0.89, CI 0.79-1.00), an indication of harm with aspirin in the not frail cohort (1.17, 1.01-1.36) and no difference seen in the relatively small cohort of 421 frail patients (1.23, 0.87-1.73). Given the inconsistent treatment effects between frailty groups, the interaction between frailty and aspirin treatment remains uncertain and merits further investigation.
The ASPREE investigators should be praised for conducting a pragmatic and well-run trial with excellent long-term follow-up (1.5% lost to follow-up) that should motivate patient-centered discussions regarding the increased risk of bleeding without clear evidence for benefit in otherwise healthy elderly patients. More importantly, the investigators studied a key clinical question in a previously understudied older population while using a functional endpoint. Older patients care about living longer free of dementia and disability and clinical trial outcomes must reflect that. ASPREE serves as a model for using a patient-centered outcome in a major cardiovascular randomized trial and should stand as an archetype for future clinical trials in the older adult population.
Based on lack of efficacy data from ASPREE, clinicians should think twice before initiating aspirin for primary prevention in older individuals. Given the signal for harm seen, it would also be reasonable to discontinue aspirin in those older patients who only have a primary prevention indication. With modern-day randomized trial evidence building against the routine use of aspirin in primary prevention, one begins to wonder if aspirin's days as a primary prevention staple are numbered.
- Lee PY, Alexander KP, Hammill BG, Pasquali SK, Peterson ED. Representation of elderly persons and women in published randomized trials of acute coronary syndromes. JAMA 2001;286:708-13.
- Dodd KS, Saczynski JS, Zhao Y, Goldberg RJ, Gurwitz JH. Exclusion of older adults and women from recent trials of acute coronary syndromes. J Am Geriatr Soc 2011;59:506-11.
- Sardar MR, Badri M, Prince CT, Seltzer J, Kowey PR. Underrepresentation of women, elderly patients, and racial minorities in the randomized trials used for cardiovascular guidelines. JAMA Intern Med 2014;174:1868-70.
- Skolnick AH, Alexander KP. Older adults in clinical research and drug development: closing the geriatric gap. Circ Cardiovasc Qual Outcomes 2015;8:631-3.
- Bernard MA, Clayton JA, Lauer MS. Inclusion across the lifespan: NIH policy for clinical research. JAMA 2018. [Epub ahead of print]
- Tinetti ME, Fried T. The end of the disease era. Am J Med 2004;116:179-85.
- Forman DE, Arena R, Boxer R, et al. Prioritizing functional capacity as a principal end point for therapies oriented to older adults with cardiovascular disease: a scientific statement for healthcare professionals from the American Heart Association. Circulation 2017;135:e894-918.
- McNeil JJ, Woods RL, Nelson MR, et al. Effect of aspirin on disability-free survival in the healthy elderly. N Engl J Med 2018. [Epub ahead of print]
- McNeil JJ, Wolfe R, Woods RL, et al. Effect of aspirin on cardiovascular events and bleeding in the healthy elderly. N Engl J Med 2018. [Epub ahead of print]
- Ridker PM, Cook NR, Lee IM, et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med 2005;352:1293-304.
- Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet 1998;351:1755-62.
- Steering Committee of the Physicians' Health Study Research Group. Final report on the aspirin component of the ongoing Physicians' Health Study. N Engl J Med 1989;32:129-35.
- Berger JS, Roncaglioni MC, Avanzini F, Pangrazzi I, Tognoni G, Brown DL. Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials. JAMA 2006;295:306-13.
- Dai X, Hummel SL, Salazar JB, Taffet GE, Zieman S, Schwartz JB. Cardiovascular physiology in the older adults. J Geriatr Cardiol 2015;12:196-201.
- Gaziano JM, Brotons C, Coppolecchia R, et al. Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE): a randomised, double-blind, placebo-controlled trial. Lancet 2018;392:1036-46.
- Rothwell PM, Fowkes FG, Belch JF, Ogawa H, Warlow CP, Meade TW. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet 2011;377:31-41.
- Rothwell PM, Price JF, Fowkes FG, et al. Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: analysis of the time course of risks and benefits in 51 randomised controlled trials. Lancet 2012;379:1602-12.
- Singh M, Stewart R, White H. Importance of frailty in patients with cardiovascular disease. Eur Heart J 2014;35:1726-31.
- Sergi G, Veronese N, Fontana L, et al. Pre-frailty and risk of cardiovascular disease in elderly men and women: the Pro.V.A. study. J Am Coll Cardiol 2015;65:976-83.
- Newman AB, Simonsick EM, Naydeck BL, et al. Association of long-distance corridor walk performance with mortality, cardiovascular disease, mobility limitation, and disability. JAMA 2006;295:2018-26.
- Afilalo J, Alexander KP, Mack MJ, et al. Frailty assessment in the cardiovascular care of older adults. J Am Coll Cardiol 2014;63:747-62
Keywords: Geriatrics, Aged, Aspirin, Activities of Daily Living, Cholinesterase Inhibitors, Risk Factors, Quality of Life, Primary Prevention, Diabetes Mellitus, Dementia, Cardiovascular Diseases, Risk Reduction Behavior, Polypharmacy, Biological Markers
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