Article Outline
In 2016, the US Preventive Services Task Force (USPSTF) provided low-dose aspirin (LDA; 81 mg/d in the United States) with a Grade B recommendation for chronic disease prophylaxis, including colorectal cancer (CRC) prevention, among US adults between ages 50 and 59 with a 10-year risk of cardiovascular disease (CVD) events of >10%.1 A Grade B indicates a USPSTF assessment that there is “high or moderate certainty that the net benefit is moderate to substantial.” This recommendation represented a significant milestone for the field of preventive medicine because, with the exception of tamoxifen for women at high risk for breast cancer, this medication was the first recommended for cancer prevention by USPSTF guidelines. However, the USPSTF concluded that the decision to initiate aspirin among those aged 60–69 should be individualized and current randomized, placebo-controlled trial (RCT) evidence in adults aged ≥70 was insufficient.
Recently, ASPirin in Reducing Events in the Elderly (ASPREE), a RCT of 19,114 apparently healthy adults (without known active cancer) aged ≥70 (whites) and ≥65 (US minorities) demonstrated a lack of an effect of LDA (100 mg/d) on the primary end point of disability-free or dementia-free survival over a mean treatment of 4.7 years.2 Surprisingly, LDA was associated with a trend toward increased all-cause mortality driven by cancer deaths, including deaths from CRC.3 In this Commentary, we review the significance of these results, potential explanations, lessons learned so far, and next steps for the field.
Significance of the ASPREE Results
The USPSTF’s recommendation for aspirin use was based on the substantial evidence base that had developed by 2015 supporting aspirin’s efficacy for the prevention of CRC,4 with perhaps the most influential data emerging from RCTs of aspirin examining long-term CRC outcomes. First, the Women’s Health Study (WHS), the largest RCT of aspirin for primary prevention of chronic disease, showed that alternate-day 100-mg aspirin was associated with a hazard ratio (HR) of 0.80 (95% confidence interval [CI], 0.67–0.97) for CRC incidence during post-trial follow-up 10 years after randomization.5 Second, in the Colorectal Adenoma/carcinoma Prevention Programme 2 (CAPP2) RCT, a preplanned secondary analysis conducted after the first participant was followed for 10 years showed that 600 mg of daily aspirin significantly decreased the risk of CRC among carriers of the hereditary CRC Lynch syndrome in the per protocol analysis (HR, 0.41; 95% CI, 0.19–0.86) and after accounting for multiple primary tumors (incidence rate ratio, 0.56; 95% CI, 0.32–0.99).6 Finally, secondary analyses of RCTs originally conducted for CVD prevention found that aspirin treatment for ≥5 years at doses of ≥75 mg/d decreased the long-term risk of CRC by 24% compared with placebo.7
Although the results of these RCTs were convincing, the findings were largely limited to younger individuals. The mean age of participants was 55 years in the WHS, 18 years in the CAPP2, and approximately 60 years in the meta-analysis of cardiovascular trials. Less than 10% of the WHS and the none of the CAPP2 population was >65 years old. Thus, the updated recommendations of the USPSTF were appropriately conservative, issuing a Grade C recommendation among adults age 60–69 and Grade I or insufficient evidence in adults aged ≥70.
With this background, the results of ASPREE were eagerly anticipated. ASPREE was originally designed to address the lack of evidence regarding the impact of aspirin on an otherwise healthy, aging population. Given emerging data that aspirin had the potential to impact multiple health outcomes, including CVD, cancer, and dementia, counterbalanced by its association with hemorrhagic complications, the ASPREE study used a primary end point, which was a composite of death, dementia, or persistent physical disability, with the goal of integrating the balance of potential risks and benefits. The combined Australia/US study recruited 19,114 adults age ≥70 (whites) and ≥65 (minorities), of which 16,703 were Australian and 2411 were American, with 56% women, 9% minorities, and 11% reporting previous regular aspirin use. Although individuals with a history of prior cancer were not excluded, participants with a life expectancy of <5 years, were not eligible. Participants were randomized at a ratio of 1:1 to 100 mg of enteric-coated aspirin or placebo. Clinical event and adherence data were collected at annual in-person visits. In June 2017, the ASPREE’s Data Safety Monitoring Board prematurely suspended the intervention phase based on their analysis that there was a low likelihood of finding a significant treatment effect on the primary end point of disability-free or dementia-free survival if the trial was continued to its scheduled end date of December 2017.
In September of 2018, the results of ASPREE were published in 3 companion articles in the New England Journal of Medicine.2, 3, 8 Participants had experienced an average treatment duration of 4.7 years. The primary end point of death, dementia, or physical disability occurred in 921 participants in the aspirin group (21.5 events per 1000 person-years) and in 914 in the placebo group (21.2 events per 1000 person-years), with a nonsignificant between-group difference (HR, 1.01; 95% CI, 0.92–1.11; P = .79).2 Surprisingly, LDA was associated with an increased risk of all-cause mortality (HR, 1.14; 95% CI, 1.01–1.29).3 Cancer deaths were the major contributor to the excess death (HR, 1.31; 95% CI, 1.10–1.56). The increased mortality was observed across cancer types, including CRC, breast, lung, stomach, and esophageal cancers. Notably, the increase in overall death in ASPREE was primarily observed among individuals without a prior history of aspirin use and among the Australian cohort, in which the background prevalence of aspirin use was much lower than in the United States. In contrast, there was a nonsignificant decrease in deaths among those with a prior history of aspirin use (HR, 0.86; 95% CI, 0.62–1.19) and among the US cohort (HR, 0.79; 95% 0.57–1.11).
Potential Explanations of the ASPREE Results
The ASPREE results sharply contrast with previous RCTs that show mortality benefits among largely younger populations after 5–10 years of aspirin initiation and the basis for the USPSTF recommendation. This unexpected increase in cancer mortality could be attributable either to an increase in cancer incidence and/or shortened survival after cancer develops in participants randomized to receive LDA. Although a detailed analysis of the impact of LDA on cancer incidence have not yet been completed in ASPREE, initial results do not seem to show that aspirin was strongly associated with higher cancer incidence (981 cancers in the aspirin group vs 952 cancers in the placebo). Because the estimated mean sojourn time for most cancers (ie, the duration between presence of a tumor and clinical presentation) is 36–60 months,9 this suggests that the observed “on-treatment” effect of aspirin on cancer mortality may largely be due to worsened survival among participants with undiagnosed cancers (tumors prevalent at the time of enrollment or early incident tumors) rather than an effect of LDA on cancer incidence and subsequent mortality.
What could explain such a discordant effect of aspirin on cancer mortality in the elderly compared with younger adults? There are several potential hypotheses (not necessarily mutually exclusive) that bear consideration.
Hypothesis 1
Aspirin may have biological effects that vary according to the timing of exposure. Aspirin may effectively prevent the initial formation of tumors by affecting pathways fundamental to tumor initiation. Given the sojourn time for a tumor, this would explain a decrease in cancer incidence that is evident only in RCTs of aspirin with long-term follow-up. In contrast, aspirin could accelerate development or spread of an in situ tumor. This would explain a short-term adverse effect on cancer mortality that would be evident only in a RCT in which aspirin was administered to population with a high prevalence of undiagnosed cancer. In ASPREE, based on the older age and higher body mass index (an established risk factor for many cancers), the population likely harbored a higher prevalence of undiagnosed cancer at trial entry than RCTs such as the WHS, which did not observe a short-term increase in cancer mortality. Such a time-dependent effect of aspirin on cancer is mechanistically plausible. For example, inflammation and/or the response to local tissue injury may predispose to the initial development of cancer. Thus, the anti-inflammatory effects of aspirin may inhibit tumor initiation, leading to subsequent decreases in cancer incidence. In contrast, for undiagnosed or established tumors, local and systemic antitumor immune responses may be critical in preventing tumor growth or spread. Thus, in the setting of an established cancer, aspirin’s anti-inflammatory effects may blunt already mobilized antitumor defenses.10
Hypothesis 2
Aspirin may have biological effects that vary according to age or other risk factors for cancer. Our understanding of the potential mechanistic differences between cancers that arise later in life compared with those that develop at younger ages is very incomplete. It is conceivable that cancers that arise in the elderly may be a consequence of pathways specific to aging (eg, epigenetic alterations) or arise from different cells-of-origin than cancers in younger individuals.11, 12 In turn, aspirin may have distinct activity in such pathways or cell types in older hosts that could have very different clinical consequences. Similarly, cancers that arise in the setting of other risk factors, such as overweight or obesity, may depend on distinct molecular pathways that are differentially susceptible to aspirin. Indeed, >75% of ASPREE cohort compared with 49% in the WHS were overweight or obese.2, 5
Hypothesis 3
Aspirin treatment within the context of a RCT may have led to unexpected consequences that would not be seen in clinical practice. For example, it is unclear how the development of cancer during the RCT might have influenced study treatment. On the one hand, if cancers developed but were not yet clinically apparent, aspirin assignment could have led to a higher prevalence of cancer-associated bleeding complications that may have directly hastened death or influenced tolerance of cancer treatment. Arguing against this hypothesis is that the initial analysis of the clinical circumstances of death available in 66% of participants does not suggest that bleeding was the precipitating cause of deaths among those adjudicated to have died of cancer.3 On the other hand, if cancer was diagnosed and aspirin treatment was suspended, this could have resulted in a possible adverse rebound effect for a tumor that was otherwise being kept in check by aspirin exposure.
Finally, there are 2 additional plausible explanations that are not related to biological mechanistic differences in either the timing of aspirin exposure (or withdrawal) or the profile of the ASPREE population compared with prior RCTs.
Hypothesis 4
The ASPREE results are an outlier and a chance finding. Although ASPREE was methodologically robust, overall mortality was a secondary end point, whereas cancer mortality was a subcomponent of this secondary end point. Thus, if the findings are scrutinized according to the most stringent standards of adjustment for multiple testing, the increase in cancer mortality does not strictly achieve statistical significance and could be interpreted as a chance finding.
Hypothesis 5
The ASPREE results represent the true effect of aspirin. This finding would imply that prior RCTs of aspirin showing the benefit for cancer incidence and mortality were flawed. Of course, the results from the WHS, CAPP2, and meta-analyses of vascular trials were based on secondary analyses of long-term follow-up and each had methodologic shortcomings. However, the suggestion that ASPREE got it “right” but the prior RCTs were “wrong” would likely implicate a methodologic flaw that was common to each of these studies so as to produce such remarkably consistent findings. Moreover, 5 RCTs in distinct patient populations have each found that aspirin decreases the risk of recurrent adenomatous polyps, the precursor to most CRCs, establishing that an antineoplastic effect of aspirin is indeed causal.13, 14, 15, 16, 17
Lessons Learned so Far and Next Steps
What do the initial results of ASPREE mean for cancer prevention in the short term? The lack of effect on disability or dementia-free survival and the possible short-term increase in mortality suggest that aspirin should not be initiated for the sole purpose of prevention of cancer (or CVD) among a healthy elderly population. However, the results should not influence already established USPSTF guidelines supporting the use of aspirin among individuals with a prior history of a vascular event (secondary prevention) or for individuals age 50–59 years with a 10-year risk of a CVD event (primary prevention) of ≥10%.1, 18, 19 It remains unknown as to whether aspirin should be discontinued among individuals >60 years of age who already take aspirin, particularly given the results in ASPREE that mortality was primarily observed among individuals without a prior history of aspirin use. Thus, the decision to discontinue aspirin for primary prevention of either CVD or CRC remains individualized, based on a discussion between patients and providers incorporating patient preferences and the current state of the evidence.
Given the overwhelming evidence of aspirin’s beneficial effects in other RCTs, the already established USPSTF guidelines supporting its use in a large subset of the population, the ongoing conduct of RCTs of aspirin in other clinical settings, including cancer survivors,20, 21, 22 as well as the large number of individuals already taking aspirin, it is imperative that we work to understand the reasons for the unexpected early findings in ASPREE. To this end, we are planning long-term follow-up of the ASPREE cohort as well as additional clinical review and in-depth characterization of the population through biospecimens collected during the trial. This will include (1) a more complete characterization of the clinical circumstances that led to death from cancer (eg, bleeding complications) as well as potential interactions with other prognostic factors, including receipt of chemotherapy among ASPREE participant; (2) assessment of the influence of potential differences in the ASPREE population beyond age, such as genetic or metabolic risk factors, on clinical outcomes23; and (3) molecular analyses of the cancers that developed in ASPREE to offer insight into the potential biological mechanisms that may underpin differences in cancers (and their response to aspirin) that arise among the elderly compared with the young.24
Longer term follow-up of ASPREE as well as other recently completed aspirin RCTs may still identify a benefit in either cancer incidence or mortality that has yet to emerge, as was the case with prior RCTs. If such a “legacy” effect of aspirin is observed and mechanistic studies support the hypothesis that aspirin may have a differential short-term effect on undiagnosed cancers (particularly among the elderly), the implications could be significant. From a clinical standpoint, this suggests the intriguing possibility that aspirin could be recommended at a younger age for a limited duration when the risk of having indolent tumors or experiencing side effects (eg, gastrointestinal or intracerebral bleeding) is lower. This recommendation would not be unlike current recommendations for short-duration antiestrogen treatment for women at high risk for breast cancer. This strategy could significantly improve the benefit–risk calculus for aspirin that could lead to a paradigm shift in population-based prevention strategies which currently lack low-cost, widely available options for most cancers.
The contrary results of ASPREE compared with prior RCTs are humbling (summarized in Table 1). It was perhaps naïve to assume that a preventive agent would offer a uniform effect across a broad population. Although much remains to be learned, the ASPREE results so far underscore our limited understanding of the biology of cancer (particularly the influence of age) and the context-dependent mechanisms by which potential preventive agents may influence initiation, growth, and spread of neoplasia. The future of successful chemoprevention that optimizes benefits and risks will likely require a more precise, potentially molecularly targeted approach that accounts for timing of intervention and the heterogeneity in the underlying biology of the host.
Study | Population | Intervention | Follow-up Time | HR (OR) or RR (95% CI) |
---|---|---|---|---|
McNeil JJ, 20182, 3 | N = 19,114, both sexes, ≥70 years (AUS/US), ≥65 years US minorities | Aspirin 100 mg/d vs placebo | Median 4.7 years | 1.01 (0.92–1.11; P = .79) for disability-free survival 1.31 (1.10–1.56; P = .002) cancer-related mortality 1.77 (1.02–3.06; P < .05) CRC-related mortality |
Cook NR, 20135 | N = 39,876, women, ≥45 years | Aspirin 100 mg qod vs placebo | Median 10 years | 0.97 (0.92–1.03; P = .31) for total cancer incidence 0.80 (0.67–0.97; P = .02) for CRC incidence |
Burn J, 20116 | N = 861, Lynch syndrome, both sexes, mean age 18 years | Factorial design: aspirin 600 mg/d vs placebo ± resistant starch | Median 4.6 years | 0.41 (0.19–0.86) for CRC incidence (per protocol) |
Rothwell PM, 20107 | N = 14,033, four RCT on CVD outcomes, both sexes, mean age ∼60 years | Aspirin ≥75 mg/d vs placebo | Median 18.3 years | 0.76 (0.60–0.96; P = .02) for CRC incidence 0.65 (0.48–0.88; P = .005) for CRC mortality |
Baron JA, 200313 | N = 1,121, previous sporadic colorectal adenomas, both sexes, mean age 57 years | Factorial design: aspirin 325 mg/d vs aspirin 81 mg/d vs placebo, ± folic acid | Colonoscopy ≥1 year after randomization | 0.81 (0.69–0.96) in 81-mg group for any adenoma 0.96 (0.81–1.13; P = .06) in 325-mg group for adenoma |
Sandler RS, 200314 | N = 635, previous CRC, both sexes, ages between 30 and 80 years | Aspirin 325 mg/d vs placebo | Median 2.6 years | 0.64 (0.43–0.94; P = .022) for adenoma |
Benamouzig R, 200315 | N = 272, previous sporadic colorectal adenomas, both sexes, mean age 57.7 years | Aspirin 300 mg/d vs aspirin 160 mg/d vs placebo | Colonoscopy ≥1 year after randomization | 0.73 (0.52–1.04; P = .08) for any adenoma 0.13 (0.02–1.02; P = .05) for adenoma ≥10 mm |
Logan RF, 200816 | N = 945, previous sporadic colorectal adenomas, both sexes, mean age 57.8 years | Factorial design: aspirin 300 mg/d vs placebo ± folic acid | Median 3–5 years after randomization | 0.79 (0.63–0.99; P = .043) for any adenoma 0.63 (0.43–0.91; P = .013) for advanced adenoma |
Ishikawa H, 201417 | N = 389, Asian, endoscopically treated adenoma and/or intramucosal CRC | Aspirin 325 mg/d vs Placebo | Colonoscopy ≥2 years after randomization | 0.60 (95% CI, 0.36–0.98) for any colorectal neoplasia |
CI, confidence interval; CVD, cardiovascular disease; CRC, colorectal cancer; HR, hazard ratio; OR, odds ratio; RR, relative risk; RCT, randomized controlled trial.
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