Aspirin Therapy May Increase Risk for Bleeding Events

Clinical Context

Aspirin is used for a wide variety of indications, and an analysis of randomized trials by Rothwell and colleagues, which was published in the January 1, 2011, issue of the Lancet, found that aspirin was effective in reducing the overall risk for death from cancer. Aspirin was particularly effective in reducing the risk for death from gastrointestinal tract cancer, and longer duration of aspirin therapy was associated with greater reductions in cancer mortality risks. However, the dose of aspirin did not appear to affect this outcome.

Nonetheless, the current study by Ray and colleagues notes that many reviews have failed to provide a balance between the risks and benefits of aspirin as primary preventive therapy. The authors address this issue, and their findings are described in the Study Highlights section.

Study Synopsis and Perspective

A new meta-analysis said to provide "the largest evidence to date regarding the wider effects of aspirin treatment in primary prevention" has shown that cardiovascular benefits are offset by an elevated risk of bleeding [1].
Senior author Dr Kausik Ray (St George's University of London, UK) commented to heartwire : "On a routine basis I would not recommend aspirin use in primary prevention. And it certainly should not be put in a polypill for mass use."
The current study did not find a significant reduction in cancer mortality. However, the lead author of a previous meta-analysis that did show a reduction in cancer death with aspirin says follow-up in the current study was not long enough to show such an effect.
The new analysis, published online January 9, 2012 in the Archives of Internal Medicine, included nine randomized placebo-controlled trials with a total of 100 000 participants. Results showed that during a mean follow-up of six years, aspirin treatment reduced total cardiovascular events by 10%, driven primarily by a reduction in nonfatal myocardial infarction (MI), but there was a 30% increased risk of nontrivial bleeding events. The number needed to treat to prevent one cardiovascular event was 120, compared with 73 for causing a nontrivial bleed.
Effect of Aspirin on Vascular and Nonvascular Outcomes or Death

Event	Odds ratio (95% CI)
Cardiovascular events	0.90 (0.85–0.96)
Nonfatal MI	0.80 (0.67–0.96)
Cardiovascular death	0.99 (0.85–1.15)
Cancer mortality	0.93 (0.84–1.03)
Nontrivial bleed	1.31 (1.14–1.50)

Possible Benefit in Those at High Risk
The authors conclude that the "rather modest benefits" and the significant increase in risk of bleeding do not justify routine use of aspirin in the primary-prevention population. They say that further study is needed to identify subsets that may have a favorable risk/benefit ratio. They note that their results suggest an increased risk of nontrivial bleeding in individuals receiving daily (vs alternate-day) aspirin treatment and a particularly unfavorable risk/benefit ratio for individuals at lower baseline cardiovascular risk.
An editorial accompanying the paper suggests that aspirin may be considered in patients with a CHD risk of more than 1% per year [2], but Ray said he thought that was an "oversimplification" of the results.
"There may be a benefit in higher-risk individuals, and there is a case for personalized medicine here. But we showed that as the event rate increased in the placebo group, the reduction in MI with aspirin also increased, but so too did the bleeding risk. The bleeding risk is always greater than the MIs prevented, but it depends on whether you think a nonfatal MI is worse than a significant bleed. So we could do better if we knew who would bleed and who would have an event. I think we need a dual risk score as is done for warfarin."
The cardiovascular results from this latest analysis are in line with those from the 2009 Antithrombotic Trialists' (ATT) Collaboration, and there seems to be agreement on the conclusions regarding heart disease. But there is less agreement on the use of aspirin for the prevention of cancer.
Disagreement Over Cancer Data

Lead author of last year's analysis showing a reduction in cancer mortality with aspirin, Dr Peter Rothwell (University of Oxford, UK) commented to heartwire : "This new meta-analysis just looks at the overall study results, and most of the studies only had three to four years of follow-up. That is not long enough to see a major effect on cancer mortality. In contrast, in our meta-analysis published last year we obtained individual patient data and followed patients long-term after the trials had finished, and in this way we were able to show a significant and impressive effect on cancer mortality."

Rothwell estimates that it takes at least five years to show an effect on cancer deaths, "but after this point you see quite an impressive effect." He noted that the new study also included both alternate and daily aspirin trials, but "all previous work has suggested that aspirin needs to be given every day to prevent cancer."
He added: "Their results are completely compatible with our results. They did show a trend toward a reduction in cancer mortality, which we believe would have become significant if they had longer-term data or if they looked at individual patient data."
The UK newspapers were today full of reports saying there is no benefit of aspirin in cancer prevention, exactly the reverse of the headlines after Rothwell's study came out last year. Rothwell says he is concerned about this. "The message today that aspirin does not prevent cancer is premature. The current study should not change advice on taking aspirin as a healthy person. It does not offer any additional information that we don't already know. We need to think about both risk of heart disease and cancer, and in general heart disease risk is coming down while cancer risk is increasing. There does appear to be a cancer benefit with long-term use, so if there is a family history of cancer I would think about taking aspirin. We have more studies with individual patient data coming out soon that will shed more light on the issue."
More Data Coming Soon
Rothwell says official guidance on primary prevention varies from country to country. "At the moment, the guidelines on primary prevention are just focused on heart disease. They have not looked at the cancer data. There are some new guidelines due to come out over the next year, and these should start to discuss the cancer findings. "
Ray, however, is not so convinced by the cancer data. "Our meta-analysis is much larger than Rothwell's. They had 25 000 individuals whereas we have more than 100 000 patients. As usual, in this situation, when you see the bigger picture, you see 'regression to the truth.' "
Ray commented to heartwire that assuming the trend toward fewer cancer deaths in the current analysis was real, the use of aspirin would produce three and half extra nontrivial bleeds for one cancer death prevented. But he suggested that the cancer data may be biased. "Cancer often shows up as bleeding, and if you are taking aspirin, you are more likely to bleed so are more likely to be investigated, which could affect survival." He also points out that Rothwell's study mixed primary- and secondary-prevention populations, while his study looked at only healthy individuals.
He added: "The cancer data are far from certain. The major reason to give aspirin is to prevent heart attacks and strokes, and in healthy people this benefit is outweighed by the risk of bleeding. Aspirin is not the same as statins, which are known to reduce mortality in primary prevention. Aspirin doesn't affect atherosclerosis; it modifies plaque rupture, which is the final step. That is why it works better in patients with established heart disease. Primary-prevention efforts are much better directed at the basics of diet, exercise, and smoking and reducing cholesterol and blood pressure."
References

1. Seshasai SRK, Wijesuriya S, Sivakumaran R, et al. Effect of aspirin on vascular and nonvascular outcomes: meta-analysis of randomized controlled trials. Arch Intern Med 2012; DOI:10.1001/archinternmed.2011.628. Available at: http://archinte.ama-assn.org/cgi/content/short/archinternmed.2011.628.
2. Mora S. Aspirin therapy in primary prevention: To use or not to use?Arch Intern Med 2012; DOI:10.1001/archinternmed.2011.626. Available at: http://archinte.ama-assn.org/cgi/content/extract/archinternmed.2011.626v1.