The results of the Aspirin in Reducing Events in the Elderly (ASPREE) trial published in the New England Journal of Medicine showcase higher all-cause mortality among apparently healthy older adults receiving daily aspirin as compared to placebo, coupled with the shocking finding of mortality being attributed primarily to cancer, thereby painting a bleak picture of Aspirin (ASA) and heralding an end to its use in primary prevention.
Previously, findings from a randomized 15,480 patient strong UK based trial, the ASCEND trial presented at the ESC 2018 in Munich, comparing Aspirin (ASA) versus placebo in diabetics, portrayed how the absolute reduction in cardiovascular events from aspirin was offset by a similar absolute increase in major bleeding, taking the wind out of the sails of this wonder drug. This was further succeeded by the results of the ARRIVE study, a randomized double-blind, placebo-controlled, multicenter study of 12,546 patients with moderate cardiovascular risk. The findings of this trial too were discouraging as Aspirin failed to show an effect on all-cause death or the cardiovascular outcome.
Finally, the results of the ASPREE trial, published online September 16 in three separate papers, served as the final blow in a series of disappointing trials. From 2010 through 2014, McNeil and his colleagues enrolled a total of 19,114 individuals in Australia and the United States who were 70 years of age or older (or ≥65 years of age among blacks and Hispanics in the United States) and were free from cardiovascular disease, dementia, or disability. Subjects were randomized to receive 100 mg of enteric-coated aspirin in one arm and placebo in the other. Deaths were classified according to the underlying cause by adjudicators who were blinded to assignments. Mortality between the aspirin and placebo groups was compared using hazard ratios and post hoc exploratory analyses of specific causes of death were performed.
“This should set the record straight. There’s a lot of folks on both sides of this but this study should end the question. There is no benefit for seniors who do not have vascular disease.”- Dr. Vincent Buffalino, M.D.
Of the total subjects enrolled, 9525 and 9589 were assigned to aspirin and placebo respectively. In the first publication, the investigators reported that the daily use of aspirin did not provide a benefit with regard to the primary endpoint of disability-free survival among older adults. Disability-free survival was a novel endpoint combining all-cause death, dementia, or physical disability, among healthy elderly individuals. The second report showed no significant reduction in cardiovascular disease but a significantly higher risk for major hemorrhage. Spurred on by these strange findings, the authors published their third analysis in the journal, evaluating the causes of death, which pointed towards cancer as the major contributor to the higher mortality in the aspirin group. A total of 1052 deaths occurred during a median of 4.7 years of follow-up. The risk of death from any cause was higher in the aspirin group as compared to the placebo group (hazard ratio, 1.14; 95% CI, 1.01 to 1.29). Surprisingly, a numerically higher rate of the secondary endpoint of death from any cause was observed with aspirin than with placebo with cancer accounting for 3.1% and 2.3% of the aspirin and placebo groups respectively. (hazard ratio, 1.31; 95% CI, 1.10 to 1.56). In response to these queer findings, Dr. Vincent Bufalino of the Advocate Heart Institute in Chicago commented, “This should set the record straight. There’s a lot of folks on both sides of this but this study should end the question. There is no benefit for seniors who do not have vascular disease.”
While John J. McNeil, MBBS, PhD, from the Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia, the lead author on all three papers, believes that this trial definitely spells the end of the role of ASA in the realm of primary prevention of cardiovascular disease. However, he also echoes a cautionary note.
It is important to contextualize these findings within the existing literature. TRITON TIMI-38, the pivotal trial of prasugrel compared with clopidogrel in ACS patients managed with PCI, showed a higher rate of cancer deaths in the prasugrel group, which was attributed by the investigators to ascertainment bias (bleeding leading to earlier or more frequent detection of tumors). The Dual antiplatelet therapy (DAPT, a combination of aspirin and a P2Y12 inhibitor) study by Mauri et al. which showed DAPT to be of benefit in patients undergoing percutaneous coronary intervention (PCI) for acute coronary syndromes (ACS) and stable coronary artery disease (SCAD) beyond 1 year after placement of a drug-eluting stent, also showed more cancer-related deaths among patients treated with continued thienopyridine as compared to placebo, a finding that may have reflected a ‘chance imbalance’ in patients with known cancer before enrolment. Multiple hypothetical mechanisms were proposed in relation to this which included true pharmacological sequelae, ascertainment bias, and survival bias. Platelet inhibition resulting in increased bleeding risk could have prompted a clinically silent cancer to become symptomatic through bleeding. Incidental detection may have occurred during an investigation carried out for bleeding which might not have occurred had the patient not been on antiplatelet therapy. Moreover, regardless of the actual cause of death, cancer would clearly be more likely to be recorded as a contributing factor than if it had not been known about. Lastly, treatment for cancer found within the study period, which might otherwise have presented later, could have conveyed elevated risks of early mortality from surgery (including procedure-related bleeding and risk of a further ischaemic event related to hemodynamic stresses or cessation of antiplatelet therapy) or chemotherapy-mediated immunosuppression.
Therefore, in the context of previous studies, the findings of ASPREE are far from expected and are a contrast to everything traditionally known about aspirin, thereby warranting a more cautioned interpretation.