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expert reaction to study looking at aspirin use in healthy people, and cardiovascular events and bleeding

A review and meta-analysis published in JAMA demonstrates that the use of aspirin in individuals without cardiovascular disease was associated with a lower risk of cardiovascular events and an increased risk of major bleeding.

Before the Headlines accompanied this Round Up.

Prof Jane Armitage, Professor of Clinical Trials & Epidemiology, Nuffield Department of Population Health, University of Oxford, said:

“This paper reports a meta-analysis of published data from trials of aspirin for preventing first cardiovascular events and includes data from the 3 most recently published large trials.  The conclusion reinforces the message from those trials that, for healthy people, the small benefits of aspirin in preventing strokes and heart attacks are counter balanced by increases in the risk of serious bleeding.”

Dr June Raine, Director of the MHRA’s Vigilance and Risk Management of Medicines Division, said:

“Aspirin is not licensed in the UK for primary prevention of cardiovascular disease and clinical guidelines do not recommend its use in this indication.

“We closely monitor all new evidence and we will carefully review the findings of this new study.  We will act quickly to provide any new information to healthcare professionals and patients if we need to.

“The risk of bleeding with use of aspirin is well recognised and clearly described in information for prescribers and patients.

“Any patients who have concerns regarding their current treatment should talk to their doctor at their next routine appointment.”

Prof Stephen Evans, Professor of Pharmacoepidemiology, London School of Hygiene & Tropical Medicine, said:

“This paper does not contain new original data but combines data from previously published randomised trials.  This combination of results from many studies means that the overall results tend to have less uncertainty than the uncertainty in the original trials.

“It examines the effect of aspirin being used at generally low doses to prevent adverse problems associated with clotting such as heart attacks.  It is well known that aspirin is effective in doing this in people who have had a recent or previous heart attack or known heart disease.  This study looks instead at those generally without obvious heart disease, including some who had diabetes.

“Aspirin reduces risks of getting blood clots, but increases risks of getting bleeding, including serious bleeding in the brain or stomach and intestine.  The balance of the heart benefit with the bleeding risk has been less certain for those without heart disease.  This analysis shows that for generally healthy people or people with diabetes but no heart disease, the benefits are small and the harms are also small and generally offset the benefits.

“They also studied overall cancer and deaths from all causes, heart disease and cancer deaths.  There was neither clear benefit nor harm for any of these, though the likelihood of benefit was greater than for harm in all-cause mortality.

“The effects are not large; the summary cardiovascular benefit was a reduction of about 4 per 10,000 participant-years with aspirin (from a rate of about 60 per 10 000 participant-years without aspirin), balanced by an increase in serious bleeding of about 6.5 per 10,000 participant-years with aspirin (from a rate of about 16 per 10,000 participant-years without aspirin).  (Note, there is a misprint in the Editorial by Gaziano, accompanying this paper, where the rate of cardiovascular outcomes is given as per 1000 instead of per 10,000 participant-years with no aspirin). The King’s College London press release tends to overstate the serious bleeding risk which although significant is not large.

“Some people will take another type of drug (called proton-pump inhibitors – PPIs) to reduce the risk of bleeding in the gastro-intestinal tract when taking aspirin.  The evidence as to whether this will make taking aspirin for its cardiovascular benefits more favourable is less clear.  The necessary large studies have not yet been done.

“The message for healthy patients is that taking aspirin has a small benefit to prevent heart disease but also at least as large a harm in terms of serious bleeding.  For some individual patients the balance may tip more clearly in either direction.

“All these benefits and harms are averages over all participants in the studies, and the actual level of benefit and harm will vary with age, having both greater benefit but also greater harm, as age increases.  This is not made clear in the paper, and the ages of participants were rather varied in the studies ranging from 40 to at least 85.”

Prof Kevin McConway, Emeritus Professor of Applied Statistics, The Open University, said:

“This is a good study, which is competent statistically.  The researchers reviewed the findings of 13 previous randomized clinical trials with, in all, over 164,000 participants, in which the participants were people who had not previously been diagnosed with cardiovascular disease (which in this context mostly means heart attacks and strokes) and were given either aspirin or no aspirin.  The researchers then used results from these trials to produce overall estimates of the effects of taking aspirin on various outcomes in such people.  In patients who have already had a heart attack or stroke, previous research has generally shown a clear advantage of taking aspirin on the chances of further cardiovascular disease, that would generally outweigh any extra risk of bleeding caused by the aspirin.  But things aren’t so clear for people who have not had such problems before.  There has been quite a lot of previous research, and indeed there have been previous reviews of research that showed evidence that aspirin does reduce the chance of new heart attacks and strokes in such people, and also showed effects on bleeding.  So why another review?  Circumstances change, because the people involved now aren’t in all respects the same as those involved in earlier studies.  They will, on average, have had different life experiences, and in particular, are more likely to have taken some other drugs such as statins.  The results from three major new clinical trials came out during 2018, and this new research was able to take them into account.

“Overall, the new research has produced results broadly in line with previous work.  For participants with no previous cardiovascular disease, taking aspirin reduced the risk of heart attacks and strokes, though perhaps not by a huge amount.  If 10,000 people without pre-existing cardiovascular disease, and otherwise like the people in these trials, take no aspirin for a year, then according to this research, about 61 of them will have a heart attack or a stroke, whether or not they recover, or will die from another cardiovascular disease.  If another 10,000 people like these take aspirin for a year, about 57 of them will have such disease.  Only 4 fewer in 10,000, but that still has some importance given how common such diseases are and how serious cardiovascular disease is.  The downside is the increase in major bleeding events, including bleeding inside the skull and brain or major bleeds in the stomach or gut.  In the 10,000 not taking aspirin, about 16 would have such an event in a year, and in the 10,000 aspirin takers, it would be about 23, or about 7 more major bleeds annually in the 10,000 aspirin takers.  That is a substantial increase, though I wouldn’t describe it as “almost 50%” as in the King’s College London press release – it’s fairer to say that it’s about 40%, and it’s important to take into account that the annual risk of a major bleed is still not high.

“So there’s evidence that aspirin does appear to reduce the risk of some dangerous diseases, while increasing the risk of some others.  Things in the studies that were reviewed have changed over time, and evidence of a benefit of aspirin on heart attack risk was not so clear in the newer studies, though benefits on the risk of strokes, and of all cardiovascular disease taken together, and an adverse effect on the risk of bleeding, were still there in newer studies.  There’s a balance to be set between the risks and benefits, and I think this new study won’t clear up existing differences of opinion on whether it’s best for people of a certain age to take daily aspirin even if they have not had previous heart disease or a stroke.  Ideally it would help to know whether some people have characteristics that make aspirin a good choice for them, while it would be better for others to avoid it.  This new research hasn’t really added to what’s known about such characteristics.  The researchers point out that different individuals will have different views, in any case, on where the balance between the risk of a heart attack or stroke compared to the risk of a major bleeding event lies for them personally, and that patients’ views on the balance of risks and benefits should be taken into account.  The excellent linked editorial by Michael Gaziano emphasises this point too.”

Prof Jeremy Pearson, Associate Medical Director (Research), British Heart Foundation, said:

“The meta-analysis by Zheng & Roddick of the relative benefit (reduction of major cardiovascular events) versus harm (major bleeding events) when taking aspirin for primary prevention valuably updates our knowledge, but does not change the current perspective.  It confirms that the average risk of harm exceeds benefit, so that guidelines should not be changed.  Nonetheless, further research to understand whether there is a subset of individuals whose bleeding risk on aspirin is low may pave the way to personalised treatment.”

‘Association of aspirin use for primary prevention with cardiovascular events and bleeding events: A systematic review and meta-analysis’ by Sean L. Zheng et al. was published in JAMA at 16:00 UK time on Tuesday 22 January 2019.

Declared interests

Prof Stephen Evans: “I have no conflicts of interest in relation to this paper.”

Prof Kevin McConway: “Kevin McConway is a Trustee of the SMC.”

None others received.

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