The ASPREE Trial and the Epidemic of CLI in Elderly Patients

Mahmood Razavi, MD, reviewed the ASPREE trial and its implications for patients with CLI at the 2019 AMPutation Prevention Symposium in Chicago, Illinois. Dr Razavi is the Director of Clinical Trials Center at the St Joseph Heart & Vascular Center in Irvine, California. His presentation covered the design and results of the ASPREE trial, as well as what the trial means for treatment of patients with CLI.

What were the goals of the ASPREE trial? 

There have been a number of studies looking at aspirin and its effects on neurodegenerative and neurocognitive disorders. Some studies have shown that aspirin has a protective effect, though not to the same magnitude as observed in cardiovascular diseases. The ASPREE trial was a primary prevention trial, which means that the patient population was healthy. ASPREE tested the impact of low-dose aspirin on disability-free survival in community-based populations. The study included over 19,000 patients who were otherwise healthy and had no preexisting neurocognitive disorders. The trial focused specifically on individuals aged 70 years or older in Australia, and 65 years or older in the U.S.    

What were the study results?

There was a follow-up period of 4.7 years, and results showed that there was no benefit of aspirin in healthy patients. These results differed from those seen in prior, secondary prevention studies that had examined the role of aspirin in patients who had preexisting disability or neurocognitive disorders, or were at risk for disease. Similarly, secondary prevention studies have demonstrated that patients with a high risk for cardiovascular disease or with preexisting cardiovascular disease show significant improvement in cardiovascular endpoints with aspirin. However, there is not a role for aspirin as primary prevention (ie, healthy patients). In the ASPREE trial, as may be expected, there was higher risk of bleeding in the healthy patients who took aspirin.  

It is important to note that risk of bleeding has been shown in other primary or secondary prevention trials, whether with anti-platelet or anti-coagulant medications. The question is, does the risk of bleeding justify the benefits? In most trials of aspirin and other antiplatelet therapies, there is a benefit, and a tradeoff. However, the ASPREE trial showed no benefit at all.

How did the ASPREE trial differ from previous trials?

The ASPREE trial was the first time that aspirin had been studied in the healthy elderly population. Additionally, this study showed no benefit in terms of disability-free survival and prevention of neurocognitive disorders. The ASPREE trial did not focus primarily on preventing cardiovascular disease, though prevention of cardiovascular disease was a pre-specified endpoint. Interestingly, there was no benefit found in terms of cardiovascular disease prevention either. 

Were there any other interesting findings from ASPREE? 

The other interesting finding in ASPREE was an increased risk of cancer-related mortality, a result that was in contrast to prior meta-analyses that had shown that there may be a net protective effect of aspirin for cancer, especially colorectal cancer.

However, in ASPREE, the risk of cancer mortality was increased, and the risk was not confined to any particular type of tumor or location. Other studies did not show such a risk, but ASPREE differed from other primary prevention trials of aspirin in terms of the patient population, which was almost exclusively elderly in ASPREE. Additionally, other studies did not include cancer mortality as a pre-specified endpoint.

Have there been any misconceptions about the ASPREE trial?

Many physicians confuse the primary prevention and secondary prevention roles of aspirin. They might hear of an abstract or summary of a paper and not realize that primary prevention means that, by definition, patients were healthy and did not have pre-existing risk factors. Secondary prevention means that the patient has had a cardiovascular event. Without a doubt, aspirin and antiplatelet therapies have a positive impact in secondary prevention, and those patients should not be denied medication.

Can we learn anything from ASPREE that may help CLI patients going forward? 

I was not involved in the trial, but I am very interested in neurodegenerative disorders in the elderly population, especially in patients with CLI. We always talk about how CLI patients are underdiagnosed and undertreated. It is interesting how we tend to ignore common neurodegenerative disorders in this patient population while we are focusing on CLI. Cardiovascular and neurodegenerative disorders are often seen concurrently in patients with CLI. From our perspective, we need to be aware of large trials such as ASPREE that have tested various theories in elderly patients. The ASPREE trial offered confirmatory evidence that aspirin has no place in a healthy patient population, but it should not change our practice with patients who have pre-existing cardiovascular disease or risk factors.

Any final thoughts?

The takeaway is that there is no role for aspirin in healthy elderly patients who have no pre-existing cardiovascular disease, disabilities, or neurocognitive disorders. However, there is a strong role for aspirin in secondary prevention of those diseases.   

Disclosure: Dr. Razavi is a consultant for Abbott Vascular, Boston Scientific Corporation, Bard/

BD, Medtronic, Microvention/Terumo, and Phillips/Volcano. He provides grant/research support for NIH, Mercator, Phillips/Volcano, and Bluegrass Vascular.

Address for correspondence: Mahmood Razavi, MD, can be contacted at mrazavi@pacbell.net