02 Oct 2018
DR STEPHANIE WARD, Monash University and Visiting Fellow with UNSW Sydney School of Psychiatry
For thousands of years the therapeutic effects of willow tree bark extract, salicyclic acid, have been well known. Refined and stabilised by Hofman in 1897, today aspirin is one of the most widely used medications. Aspirin reduces inflammation, and because it also has an effect on blood clotting it is a mainstay of treatment for cardiovascular diseases such as heart attack and stroke, and for the prevention of recurrent stroke and heart attacks in people whom have already experienced these - what is termed “secondary prevention”.
However, of the millions of people around the world who regularly take aspirin, many are healthy. Numerous studies have evaluated the relative benefits and risks of aspirin in healthy people - for what is termed “primary prevention”. The first studies showed benefit, but more recent studies have shown less impressive results. This is partially because healthy persons are at a low risk of having significant cardiovascular events, and any small beneficial effect in preventing a cardiovascular event can be offset by the small, but increased risk of significant risk of bleeding associated with aspirin use. As a result, guidelines about aspirin in primary prevention differ. Some recommend aspirin for groups with high baseline risks of cardiovascular disease, but all recommend that these risks must be balanced against the risks of bleeding.
Until now, there have not been any studies evaluating the risks and benefits of low dose aspirin in healthy older adults. This is despite this age group having both the highest incidence of cardiovascular disease, and the highest risk of bleeding complications. The ASPirin in Reducing Events in the Elderly, “ASPREE" study, led by Monash University, was a large, randomised controlled trial designed to definitively answer this question. 19, 114 men and women, aged 70 and over, or 65 and over from minority groups in the United States, were randomised to receive either low dose aspirin or placebo and were followed for nearly 5 years, for the combined primary outcome of death, disability or dementia. Cancer, cardiovascular disease and death were secondary outcomes.
The results of ASPREE were published as three papers in September 2018 in the New England Journal of Medicine. There was no benefit found for low dose aspirin in extending disability-free and dementia-free survival in older adults. Not surprisingly, there was an increased risk of major bleeding in the aspirin treated group, but what was surprising was that there were no significant benefit seen in the aspirin arm on any of the cardiovascular outcomes.
Another unexpected outcome was that the number of deaths was marginally higher in the aspirin treated group, and that this was mostly due to deaths from cancer. The latter is even more interesting because earlier studies suggested aspirin might be protective against cancer. However, the authors explain that while there were a higher number of deaths in the aspirin arm, it did not meet statistical significance, meaning it can’t be proven not to be due to chance. Regarding cancer, other studies that have found a benefit have reported that these emerge after more longer-term treatment with aspirin (>5 years). Finally, the number of deaths overall, and indeed any of the health outcomes, was low in both groups, reflecting the fact that the study population was a relatively healthy one. In fact, part of the reason for the lack of effect of aspirin may reflect better treatment in managing other cardiovascular risk factors, such as high blood pressure and cholesterol, so that any additional benefits aspirin provides are trivial.
So what does this mean for patients taking aspirin? Well it’s again important to emphasize that these results do NOT apply to people who are taking aspirin for secondary prevention. But for older adults who are otherwise healthy, it is worth consulting with their doctor to determine whether there is any merit in continuing. Certainly the ASPREE study now provides a solid evidence base to guide the judicious use of aspirin for primary prevention.
The ASPREE study has also a number of sub-studies that are yet to report their findings, including studies examining the effects of low dose aspirin on fractures, macular degeneration, and cognitive decline. A large longitudinal study of the Australian study participants, the “ALSOP study”, and a large Biobank also provide a valuable resource for studying healthy ageing well into the future. The results of ASPREE will certainly change practice worldwide, and contribute to clinical care that puts the well-being of older adults at the forefront.
CHeBA’s Co-Director Professor Henry Brodaty and head of the Memory Disorders Clinic at the Prince of Wales Hospital notes the major impact on clinical practice that these three papers published in the world’s leading medical journal from a large 5-year study funded by the NIH, will have.
“Cardiologists frequently recommend healthy people at risk of heart disease and stroke to take aspirin prophylactically to prevent these occurring. The risks of bleeding were seen as small compared to the benefits,” says Professor Brodaty.
“Now, we need to rethink this.”
CHeBA’s Co-Director Professor Perminder Sachdev and Clinical Director of the Neuropsychiatric Clinic says that this trial is a major contribution to clinical medicine and answers a long-standing question about the role of aspirin in the primary prevention of cardiovascular disease.
“While the primary findings of the study have been reported, there will be some secondary analyses to see if some individuals do benefit, and what their profile might be. More importantly for us, future follow-up of these study participants will tell us if aspirin prevents cognitive decline and reduces the incidence of dementia,” says Professor Sachdev.
Note that this study did not evaluate the benefits or otherwise for secondary prevention. There may still be benefit for those who have had a heart attack or a stroke in preventing recurrence. It would be unwise for patients to take themselves off aspirin without discussing with their doctor.