Aspirin: what do we know so far? What is new this week?

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1 Aspirin: what do we know so far? What is new this week? This article discusses the data published this week on the harms of low-dose aspirin, and particularly the harms with increasing age. It also looks at the benefits of aspirin in cardiovascular disease and for cancer, and discusses some of the concerns about PPI use with aspirin. I am well aware that for non-cardiac vascular disease, clopidogrel, or an alternative agent, is now usually first line. But of course the longest and largest data comes from the aspirin trials, and hence the focus on aspirin. Aspirin in CVD: benefits The best data on the benefits of aspirin in CVD comes from the ATTC trials (Lancet 2009:373:1849 & 1821). For secondary prevention of CVD, compared with no treatment: o You need to treat 66 people with aspirin daily for 1 year to prevent 1 CV event (NNT 66/y). o You need to treat 344 people every day for 1 year to prevent 1 CV death (NNT 344/y). These NNTs indicate we should offer aspirin (or an alternative antiplatelet) for secondary prevention of CVD. For primary prevention of CVD, compared with no treatment: o Aspirin is no longer used for the primary prevention of CVD because the benefit is too small. You need to treat 1666 people with aspirin daily for 1 year to prevent 1 CV event (NNT 1666/y). High-risk individuals (hypertensives, diabetics) do not get significantly more benefit than low-risk individuals. There is no reduction in CV mortality with aspirin use in primary prevention. Aspirin in CVD: harms Harms of low-dose aspirin: o For every 3333 people treated with aspirin for 1 year, there would be 1 additional significant bleed (NNH 3333/y) (Lancet 2009:373:1849 & 1821). However, the latest data suggests the risks depend on age. This large UK-based population cohort study of those who had had a CV event (TIA, ischaemic stroke, MI) assessed the harms from antiplatelets (mainly aspirin). The strength of the research is that it looked at risks based on age (Lancet 2017, doi.org/ /s (17) ). The study showed: The harms of aspirin increase with age. o The risks were as follows (note the different age ranges in the right-hand column): Annual risk of major bleed <75y 85y Risk of major bleed/year 1% 4% Cumulative risk over 10y <75y 75y Risk of a major GI bleed over 10y 2% 9% Risk of major intracranial bleed over 10y 1% 3% The risk of minor bleeds was similar across all age groups. The outcomes after such events were also worse in older people: bleeds were 10x more likely to be disabling or fatal in those aged 75y or older. This is an important shift in thinking: until now, GI bleeds were considered to rarely be associated with significant long-term harm. Mitigating the risks with PPIs The researchers estimated the benefits of PPIs based on the only published meta-analysis of relevant RCTs, and found that for those taking aspirin for CVD secondary prevention: PPIs offer significant benefits in the older population who are taking aspirin: o For those under 65y: you need to treat 338 people with a PPI daily for 5y to prevent 1 disabling or fatal GI bleed. o For those over 85y: you need to treat 25 people with a PPI and aspirin daily for 5y to prevent 1 disabling or fatal GI bleed. On the basis of this data, the authors suggested that age 75 would be a good time to suggest starting a PPI in those requiring antiplatelets.

2 Do PPIs inhibit the action of aspirin? Possibly! Some data from cohort studies suggests that PPIs impair aspirin function (remember, cohort studies only show associations, not causation) (BMJ 2011;342:d2690). In those who had had an MI, those on aspirin and a PPI, compared with aspirin alone, were at increased risk of reinfarction. This applied to all the PPIs. The risk increase was small (a 1.5-fold increase in CV events/death as a composite endpoint). H2RA did not increase the risk of re-infarction. The mechanism of action may be through affecting aspirin absorption by changing the acidity of the stomach or interfering with aspirin s ability to interact with platelets. No one is suggesting we stop using PPIs with aspirin, but perhaps we should only use them if there is a good indication (and age may be one of those indications, based on the data above). In addition, there are other concerns about PPIs (these are discussed in more detail in the Gastroenterology chapter on Aspirin for cancer Aspirin for cancer prevention (Annals Oncol 2015;26:47). Aspirin reduces incidence of, and mortality from, cancer. For every 29 people over the age of 55y who take aspirin for 5y, there will be 1 less cancer death 20y later. Aspirin has the greatest impact on colorectal, oesophageal and gastric cancers. It has a weaker impact on lung, breast and prostate cancer. After the age of 50, the benefits seem to build over time, being greatest after 10y of aspirin use, and continuing even when aspirin is stopped. No benefits are seen before the age of 50. Harms increased with age. Benefits were slightly greater in men than women, and also increased with increasing age. If 1000 people take aspirin daily from age 55y for 10y and then stop, at aged 75y, compared with no aspirin, there will be: Benefits Harms 16 fewer cancer deaths 1 less heart attack Aspirin has also been shown to: 1 fatal stroke 1 fatal GI bleed Reduce distant metastatic spread, but not local or regional spread. The benefit was greatest for GI cancers (Lancet 2012;379:1591, Lancet Oncol 2012;13(5):518). Prevent colon cancer. NNT=57/5y (57 people have to take aspirin for 5y to prevent 1 death from colon cancer) (Lancet 2010;376:1741 (few women in this trial)). The Women s Health Study showed reduced colon cancer incidence, but not mortality, with 100mg aspirin on alternate days (Ann Int Med 2013;159:77). Reduce mortality in those with established colon cancer. NNT=20/10y (20 people diagnosed with colorectal cancer have to take aspirin for 1 extra to survive 10y) (JAMA 2009;302:649). What dose? There have been no head-to-head trials comparing different doses of aspirin in cancer, but doses as low as 75mg have shown benefit. Higher doses have not shown clear additional benefits, but are known to increase the risk of harm (Annals Oncology 2015;26(1):47). For how long? For cancer prevention, incidence starts to fall after 3y, and mortality after 5y. (Annals Oncology 2015;26(1):47). Why might aspirin prevent cancer? Aspirin inhibits COX-2 which is expressed in some tumours. So would you take aspirin for cancer prevention? There is no national guidance suggesting people use aspirin for this indication. However, when we teach this research on our GP Update courses, about 50 70% of our audiences indicate that if they were 55 years old, and had no contraindications, they would be inclined to take low-dose aspirin for cancer prevention. What does all this mean in practice? Aspirin should NOT be used in primary prevention of CVD, even in high-risk populations such as hypertensives and diabetics.

3 Aspirin (or an alternative antiplatelet) should be used in secondary prevention of CVD, provided there is not a good contraindication. Aspirin reduces the risk of cancers, particularly GI cancers. However, there is no national guidance suggesting people use it for this indication. When aspirin is used, the risks of major bleeds increase with age, and the outcomes are much worse with a 10- fold increased risk of a disabling or fatal outcome after a significant bleed in those over 75y compared with those under 75y. PPI use reduces the risk of significant bleeds in those on aspirin, and the benefits are much greater in older people who are at highest risk. On the basis of this data, the authors suggested that age 75 would be a good time to suggest starting a PPI in those requiring antiplatelets. How about auditing those on aspirin (and perhaps other antiplatelet agents) aged 75 and over to see how many are on PPIs? TH FI Aspirin in CVD prevention and cancer Aspirin is no longer used in primary prevention of CVD as the benefits are too small (NNT 1666/y). This also applies in high-risk primary prevention populations such as those with diabetes and hypertension. Aspirin is beneficial in secondary prevention (NNT 66/y to prevent 1 CV event, NNT 344/y to prevent 1 CV death). The harms from aspirin have been considered to be low, but recent evidence suggests that the risk increases with age, and any adverse events have much greater consequences in older people with a 10-fold risk of disability/fatal outcomes after a significant GI bleed in those aged 75 and over. PPI use reduces the risk of significant bleeds in those on aspirin, and the benefits are much greater in older people who are at highest risk. On the basis of the latest study, the authors suggest that those aged 75 and over on aspirin should be on a PPI. Aspirin reduces the risk of cancer: for every 29 people over 55y treated with low-dose aspirin for 5y, there will be 1 less cancer death at 20y. However, this is not part of any national guidance (yet!). You could audit those on PPIs aged 75 and over who are on aspirin (and perhaps other antiplatelet agents) to see how many are on PPIs. MN My notes leave blank We make every effort to ensure the information in these pages is accurate and correct at the date of publication, but it is of necessity of a brief and general nature, and this should not replace your own good clinical judgement, or be regarded as a substitute for taking professional advice in appropriate circumstances. In particular check drug doses, side effects and interactions with the British National Formulary. Save insofar as any such liability cannot be excluded at law, we do not accept any liability for loss of any type caused by reliance on the information in these pages. GP Update Limited June 2017

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