The end is nigh for using aspirin in primary prevention among older adults.
The latest findings from the long-spanning ASPREE study add yet another nail in the coffin of the proposed protective effects of daily low dose aspirin.
Previous data from the Aspirin in Reducing Events in the Elderly (ASPREE) trial suggested there was no difference in the incidence of cancer between patients receiving daily low-dose aspirin or placebo after a median follow-up of 4.7 years.
There is little evidence on the association between daily aspirin and cancer outcomes in older adults in the longer-term.
Now, data from the observational extension of ASPREE (ASPREE-XT), suggests that extending the follow-up period to a median 8.6 years also failed to show an association between aspirin and cancer incidence in older adults.
“Given the longer follow-up, we thought that would be a long enough timeframe to see if anything had changed,” said Associate Professor Suzanne Orchard, senior research fellow in the School of Public Health and Preventive Medicine at Monash University, director of the ASPREE-XT study and lead author on the new research.
“But we didn’t see any change in cancer incidence rates over the long-term.”
The follow-up of the ASPREE trial, published in JAMA Oncology, involved over 14,000 individuals who survived and remained cancer free at the end of the original ASPREE study period.
Participants did not continue to take the medication they were randomised to for the ASPREE-XT component of the study. There were 3448 incident cancers detected over the course of the follow-up, along with 1173 cancer deaths.
After a median follow-up of 8.6 years, there was no association between low-dose aspirin and overall cancer incidence (hazard ratio 0.98, 95% confidence interval 0.92-1.05).
There was also no association between aspirin intake and all solid tumours both at an overall (HR 0.99, 95% CI 0.92-1.06) and stage-specific level, nor was there an association between aspirin use and the incidence of prostate, colorectal, breast, lung and bladder cancer.
There was, however, a potentially protective association between aspirin and melanoma incidence (HR 0.77, 95% CI 0.62-0.94).
The association between aspirin and mortality was a slightly different story, with people in the aspirin group being 15% more likely to die following an incident cancer event compared to people in the placebo arm of the trial.
Again, there was no association between aspirin and cancer-related mortality when cancer stage and location were considered. The lack of an association with cancer stage contrasts the findings from the original ASPREE RCT, where aspirin increased the risk of stage 4 cancer incidence.
“Whilst we did still see the elevated cancer-related mortality risk – it was lower than it was at the end of the clinical trial phase, it had dropped down to 15% – when we restricted our analysis to the follow-up phase where participants weren’t taking the study medication, we didn’t see any cancer-related mortality risk at all,” said Professor Orchard.
“So, we believe that the long-term cancer risk that we’re seeing is just a leftover effect from the clinical trial phase and is slowly dissipating over time.”
Over the last decade, research spawning from the original ASPREE RCT and its observational extension, ASPREE-XT, has found no association between daily low-dose aspirin and: promoting a healthy lifespan, reducing the risk of all-cause mortality (it increased it by 14%), stroke (but it increased the risk of intracranial bleeding), fractures (aspirin increased the risk of serious falls), major gastrointestinal bleeds (it also increased this risk) and major adverse cardiovascular events (another increase in risk, as well as the risk of major haemorrhage), slowing the decline in global cognition associated with obstructive sleep apnoea as well as slowing age-related declines in kidney function and hearing loss, reversing frailty among prefrail and frail individuals.
However, daily low-dose aspirin was found to reduce the incidence of type 2 diabetes.
Professor Orchard said there was “no doubt” that older adults should refrain from starting daily doses of aspirin for primary prevention purposes.
“The bulk of the evidence [around aspirin] is derived from middle-aged cohorts. But recent trials like ours, the ARRIVE study and the ASPIRE studies focus on older people. The first primary findings from these three studies all came out around 2018, were the first time that older adults had been looked at with low dose aspirin,” she said.
“And the main take home message is that just because aspirin works in a middle-aged cohort in a particular way doesn’t mean it’s going to work the same way in an older person. I guess that’s the general view with any medication, and it points to the fact that there are changes in the body that alter the way cancer operates in older people compared to younger people, and so on.”
Other studies exploring the potential association between aspirin use and cancer incidence/mortality have yielded mixed results, with some studies suggesting the age of the patient – and the age they start taking aspirin – could influence the treatment’s effects.
“A differential effect of aspirin according to age is biologically plausible,” the researchers wrote.
Related
“Although the precise anticancer mechanisms of aspirin have not been established, leading hypotheses include inhibition of prostaglandin synthesis and platelet-derived thromboxane A2 (TXA2), which has recently been shown to be a suppressor of T-cell function.
“In older adults such as those in the ASPREE population, age-related declines in immune function (immunosenescence) and age-related low-grade chronic inflammation (inflammaging) may attenuate aspirin’s anti-tumoral effects.
“It is even plausible that the increase in late-stage cancer and cancer mortality seen with aspirin in ASPREE may reflect a potential detrimental effect of aspirin according to biological context, such that aspirin may paradoxically blunt immunosurveillance in the setting of the immunosenescence or inflammaging.
“Finally, pathways and genetic variational profiles driving cancer biology change with age, potentially resulting in a different aspirin response compared with cancers in younger individuals.”
The fact that there are some questions that still need to be answered isn’t deterring major organisations from winding back recommendations about which individuals should start taking aspirin on a daily basis.
“The Australian Cancer Council had previously recommended low-dose aspirin [in older adults], but they have now modified their guidelines to restrict it to patients aged 60-69, and then recommend that anyone over the age of 70 should have a discussion with their clinician about whether starting low-dose aspirin is a wise thing to do,” Professor Orchard said.
“And then the United States Preventitve Services Task Force, one of the bigger guideline committees [in the world], had a set of guidelines in 2016 that said you should take low-dose aspirin for colorectal cancer prevention, because that’s the cancer subtype where the evidence is strongest.
“And in 2022 they withdrew that recommendation for low-dose aspirin for colorectal cancer in people over 70 on the basis of those three main trials and a few other studies that showed a lack of benefit and potential risk in that cohort. So, guidelines are changing.
“In fact, the USPSTF put out a call for more research with respect to low-dose aspirin and colorectal cancer in people over 70 that go for longer than 10 years. They feel that the story is not quite clear, and they recognise that the potential benefits and risks will take a while to manifest.”
Plans to continue researching the longer-term effects of aspirin in older adults through another extension of the ASPREE study are already underway.
“I’m very pleased to report that we’ve got money from the National Cancer Institute in the US to continue with a third phase of the study, and to follow participants for another five years. That will take us beyond the 15-year mark [in terms of follow-up duration], which I think will allow us to have some really strong evidence at that timepoint and more certainty about what we are seeing,” Professor Orchard said.
“The new phase will be called ASPREE-LT, which stands for long-term. We’re hoping to start contacting participants in the next few months, consenting them back into the study and then following them by phone call every year and collecting their health event data again.”
Professor Orchard also emphasised an important caveat when considering the results of the current study.
“We don’t want people who have been prescribed aspirin by their healthcare provider, for reasons such as secondary cardiovascular disease prevention, stopping [taking aspirin] in a panic. If they’re uncertain, they should have another conversation with their GP,” she said.
“But this study is for older people who initiate aspirin as a primary cancer prevention strategy, so the results can only be looked at in that framework.”
