Is aspirin coming to the end of the road in primary cardiovascular prevention? Maybe, but expect a raft of trial results before it's decided, says Gavin Atkin
Is the tide turning for aspirin in primary prevention of cardiovascular disease? It certainly seems so after the past couple of months. First, in September, Scottish officials writing draft guidelines decided they could not recommend aspirin for primary prevention in diabetes patients because recent trials had increased uncertainty about its role. The Scottish Intercollegiate Guidelines Network (SIGN) observed that in two studies aspirin had failed to show a significant reduction in cardiovascular outcomes. Both studies, said the SIGN guideline authors, should be considered in the context of the HOT study, published in the late 1990s, which showed a significant increase in major bleeds in patients receiving aspirin.
Then, in October, the drugs regulator MHRA issued a drugs safety update reminding healthcare professionals that aspirin was not licensed for primary prevention of vascular events. And as C+D went to press this week, the Drug and Therapeutics Bulletin called for the abandonment of aspirin in patients yet to develop "obvious" cardiovascular disease (see p6). Yet it was only in March that the US Preventative Services Task Force came out strongly in favour of aspirin in primary prevention - and even described the strength of the evidence as "grade A".
So what's going on here? The fact is that while there is little or no argument about the usefulness of aspirin in secondary prevention, the idea that this cheap, widely available antiplatelet drug is also effective in preventing a first myocardial infarction (MI) or ischaemic stroke has had a much rougher ride going back at least as far as the late 1980s. It's also true that aspirin has taken some particularly big knocks in the weeks between the US recommendations and the recent spate of contradictory advice.
Initial interest came in the early 1980s, when it was found that the antiplatelet effects of aspirin might benefit patients with heart disease, says Oxford University epidemiologist Professor Colin Baigent. "Long-term studies in people with a previous heart attack showed it was effective in preventing recurrences," says the Medical Research Council- sponsored researcher. "So then people wondered about primary prevention: could we prevent a first event in people who are apparently healthy? If aspirin is so good at preventing a second event wouldn't it be even better if it prevented a first event?"
The first studies were done in physicians: the British Doctors Study and the US Physicians Health Study. The smaller British study produced a negative result, but the American study was strikingly different - it showed such large reductions in rates of first MI that it was discontinued early. Figures from the trial showed a 44 per cent reduction in risk of MI and a small rise in stroke risk that did not reach statistical significance.
The appeal of this cheap, widely available drug that could save lives was clearly strong. However, researchers have often been unable to agree on the answer to the question of whether the increased risk of gastrointestinal bleeds and intracerebral haemorrhage noted by HOT cancels out the reduced risk of MI and ischaemic stroke. Nevertheless, for some time the accepted view was that diabetics were at such high risk of cardiovascular disease that they should be treated as if they already had it - and should be treated with aspirin.
But three new studies have raised a big question mark over the use of aspirin even in high risk groups. The first two - the POPADAD study in Scottish diabetics published in October last year and the JPAD study in Japanese diabetics published a few weeks later - were both carried out in patients with no evidence of heart disease, and neither showed a difference between aspirin and control. "When taken together with other evidence in people with diabetes, it was perceived that the evidence for taking aspirin in patients with diabetes who are at low risk was pretty weak," says Professor Baigent.
The third study, from Professor Baigent's own group, added still further to the evidence - and seemed to bring some new understanding to the issue. "What we did was to look at studies that have been completed in people that appear to be healthy. We brought together all the data that was in those trials, which included 95,000 subjects, and re- crunched it.
"We found that the pattern of effects of aspirin in primary and secondary prevention are similar: in each case the relative reduction in risk of a heart attack is about a quarter. But because the absolute risk in primary prevention is an order of magnitude smaller, the benefit of taking aspirin is also much smaller."
In fact, the figures show that the absolute reduction in mainly non- fatal heart attack is about twice as big as the increase in absolute risk of bleeding. If that's true, why not use it?
It is true, says Professor Baigent, but the issue is more complicated. The reason why aspirin treatment to prevent cardiovascular events in large numbers of patients would be inappropriate is partly a matter of scale but also down to the evidence for other ways of preventing cardiovascular events: "The problem is that - just like giving a vaccine on a large scale - if one is going to use aspirin for primary prevention on a large scale you want to be really sure it's safe.
"But more than that there are now much safer ways to reduce risk in the general population. Obviously we'd recommend people give up smoking, but if they're not a smoker in these times the obvious treatment to reduce risk would be statin therapy.
"Statins have been reliably demonstrated to reduce both fatal and non- fatal heart attacks and, although they can cause rhabdomylosis, it's extremely rare. It makes more sense to begin your primary prevention with a statin and a blood pressure lowering drug if that can be tolerated, and only then to consider whether aspirin is appropriate."
Now here's the rub: if before you start considering aspirin you have already reduced the patient's risk of an event possibly by as much as a half using lipid lowering and antihypertensive therapies, then the balance of risks and benefits of adding aspirin are likely to be equal - numbers of additional bleeds and haemorrhages are likely to be roughly comparable with the numbers of prevented MI and ischaemic strokes. In effect, it becomes still harder to see how the reduced benefits of aspirin treatments can justify aspirin's negative effects, says Professor Baigent.
"It's a drug that has very small benefits and very small hazards, and they seem to be about the same size. So it doesn't make sense to use it for primary prevention in large sections of the population," he concludes.
Professor Baigent's analysis found another interesting point, he reveals. "In previous exercises where people have brought together modelling evidence, it has been assumed that the risk of bleeding has been relatively constant in different groups.
"By pooling the data from different studies we've shown that to be a really gross miscalculation - it turns out that the risk factors for heart attacks are largely the same as those for both gastrointestinal bleeds and intracerebral haemorrhages, so the very people who stand to gain most from aspirin also stand to lose most."
But that's not the end of the story for aspirin - not by any means. A powerful body of opinion continues to support aspirin, as the US Preventative Services Task Force guidelines published earlier this year show. Also, there are a number of upcoming studies in patients with diabetes designed to identify groups of high risk diabetes patients who might benefit from aspirin. These are expected to throw more light on the issue in the next several years: the ASCEND trial looking at both aspirin and fish oils in diabetes has been underway since 2004; the Italian ACCEPT-D trial examining the benefits of aspirin and statins has begun more recently; the US National Institute of Health is running the ASPREE study of aspirin in the elderly; and aspirin manufacturer Bayer is sponsoring the ARRIVE study of aspirin in a range of patients at high risk of cardiovascular events.
However, Professor Baigent believes he already knows what many of these studies will find, given the conclusions of his own work. "My own prejudice is that where risk of MI is high, risk of gastrointestinal bleeding and intracerebral bleeding is also high and that this will prevent a clear answer from emerging, particularly if the patients are already using a statin or blood pressure lowering drug to reduce risk."
* Scottish Intercollegiate Guidelines Network (2009)
Open consultation on the draft guideline on the management of diabetes. www.sign.ac.uk/guidelines/drafts/index.html
* Antithrombotic Trialists (ATT) Collaboration (2009)
Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials, Lancet 373: 1849-60.
Need to know: advice for healthcare professionals
* Results of recent studies lend support to the licensed indications for aspirin in secondary prevention of vascular events only.
* Aspirin is not licensed for the primary prevention of vascular events. If aspirin is used in primary prevention, the balance of benefits and risks should be considered for each individual, particularly the presence of risk factors for vascular disease (including conditions such as diabetes) and the risk of gastrointestinal bleeding.
Source: Drug Safety Update, MHRA, October 2009
Copyright: UBM Information Ltd.
"CLINICAL: A change of heart." Chemist & Druggist (2009): 25. Academic OneFile. Web. 10 Dec. 2009.
Gale Document Number:A211623757
Disclaimer:This information is not a tool for self-diagnosis or a substitute for professional care.
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