COMMENTARY

Large Trials Cast Doubt on Low-Dose Aspirin's Benefits

David J. Kerr, CBE, MD, DSc, FRCP, FMedSci

Disclosures

February 20, 2019

This transcript was edited for clarity.

Hello. I'm David Kerr, professor of cancer medicine at the University of Oxford. As many of you know—those who listen to my small rants on Medscape from time to time—I have been conducting a long-distance love affair with aspirin for some time in terms of its cancer-preventive properties.

I have to say that this love affair has been strained somewhat by the recent publication of two important pieces. One was published in the Lancet, written by Peter Rothwell and colleagues, and the other is a report of a combined Australian-US trial in the New England Journal of Medicine.

First, let's discuss Peter's study.[1] Dr Rothwell and his colleagues suggest that there is not a single dose of aspirin, a one-size-fits-all dose, in terms of its cancer- or cardiovascular-preventive properties. They analyzed an enormous dataset from a large series of randomized trials, databases he has been successfully working on for some time. They investigated the benefits and disadvantages of aspirin according to height and weight, predominately weight. They found that the benefits of low-dose aspirin, 75-100 mg daily, in terms of cardiovascular prevention, were relatively confined to those who weigh less than 70 kg.

In the analyzed studies, the vast majority of men, 80% of whom were 70 kg or more, had no obvious benefits from aspirin at all. That's interesting. What was, for me, more worrisome was when they started to look at the disadvantages. They found that subjects taking low-dose aspirin who were under 70 kg had real possibility of harm—an increased incidence of early cancer. This is particularly pronounced in those patients who are more than 70 years old.

They concluded that we should further explore the dose of aspirin. The clinical pharmacology of aspirin has been studied since the late 1960s. There is a relationship between pharmacokinetics, steady-state plasma concentrations, weight, and age. As we grow older, liver function deteriorates, and therefore we clear drugs less effectively. This could potentially underlie what is happening. We need more mechanistic work to understand this better.

For me, a man in my late 50s or early 60s—you can decide which—who is around 80 kg, there is a real question mark as to whether I'm going to accrue any benefits from taking aspirin. Certainly, once I hit the age of 70, I should probably stop.

This is further emphasized by the ASPREE study that came out a few weeks later in the New England Journal of Medicine.[2] It's a very well-conducted randomized trial in which elderly patients, aged 70 years and above, were randomized to receive low-dose aspirin 100 mg or placebo. They recruited about 20,000 patients, 10,000 to each arm of the study. Patients were followed for all-cause mortality. Because they had high-quality death certification data, they were able to break down cause of death with a fair degree of accuracy. They also evaluated cancer-associated mortality as a secondary endpoint.

They showed that in an elderly patient population, which had been somewhat understudied in the past, low-dose aspirin brings only disadvantages. It brings only harm. The majority of that harm is caused by an increased incidence rate of cancer in the patients who were exposed to low-dose aspirin. They've said nothing about weight so far.

They admit that the follow-up is relatively long. Certainly, in terms of epidemiologic and observational work that's been reported before, the benefits of aspirin in terms of reducing the incidence of cancer seem to be somewhat delayed until after the first 5 years of taking the drug. We have to watch and see what's happening.

How do we interpret these data? I was a bit disappointed in the authors of both papers because they did not offer those of us who are taking aspirin any immediate advice. I think they should have done that. Of course, it's easy for us, as physicians, to say that we need more data, we need to understand the plausible biology better, and we need better follow-up. We need more, more, more.

There are millions of us taking low-dose aspirin around the world, even as we speak. What should we do? I think it's difficult to answer. I could lose weight or I could double the dose of aspirin and take 100 mg twice daily. That would make some form of pharmacokinetic sense. However, there's no evidence for that. I think I'm going to sit tight, at least until I'm 70, and then I'm probably inclined to stop.

We'll see what happens in terms of some large, randomized, placebo-controlled studies, which should be reporting this year or next year and may throw further light on this problem. Certainly, [we need more information] in terms of weight and in terms of age, regarding the possibility that starting aspirin later in life may increase cancer incidence.

I'm sitting tight. I'm waiting, watching, and observing. I promise that if new data become available, I'll come back to Medscape, perhaps with greater clarity of advice than I can offer at the moment.

These two interesting and important studies show, as always, that as information evolves, knowledge changes and so must our response to it. I'd be very interested in any comments that you might have on either of these two important papers and on what you plan to do in terms of your aspirin usage.

Thanks for listening. For the time being, Medscapers, over and out. Thank you.

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