Aspirin for primary prevention has “uncertain net value” according to the latest report from the Antithrombotic Trialists’ (ATT) Collaboration in the Lancet.
The new meta-analysis includes data from 95,000 primary prevention patients and 17,000 secondary prevention patients. Previous attempts to analyze existing studies did not include patient-level data, so were unable to assess the risk and benefits in prognostically important groups. “Current guidelines,” the authors write, “largely ignore any differences in bleeding risk, and recommend that aspirin be used widely for primary prevention in those at moderately raised risk of coronary heart disease,” or recommend that aspirin be used in all people at a certain age.
The new analysis found that “even for people at moderately increased risk of coronary heart disease, the major absolute benefits and hazards of adding aspirin to a statin-based primary prevention regimen could still be approximately evenly balanced.” According to the authors: “A non-fatal stroke or heart attack is more likely to result in long-term disability than is a non-fatal gastrointestinal (or other extracranial) bleed, but in primary prevention the net absolute reduction in disabling or fatal occlusive events is likely to be small, and at least partially offset by a small increase in serious intracranial and extracranial bleeds.”
The authors note the importance of having a strong evidence base for public health recommendations: “drug safety (like vaccine safety) is of particular importance in public health recommendations for large, apparently disease-free populations; there should be good evidence that benefits exceed risks by an appropriate margin.”
An accompanying editorial by Ale Algra and Jacoba Greving (Utrecht, Netherlands) is critical of the ATT report because it does not offer separate recommendation for men and women as they “reasoned that the proportional reduction in specific vascular outcomes did not differ significantly between men and women when adjustment for multiple comparisons was made.” The Dutch writers believe that a patient’s sex should be taken into consideration when considering aspirin for primary prevention, and include a chart with separate recommendations for men and women.
Harlan Krumholz provided the following comment to CardioBrief.
“Very important study that puts the risks and benefits of aspirin in perspective, supports the conservative recommendations of the US Preventive Task Force and illuminates the complexity of the decision about who should take aspirin for primary prevention. All medications have risks and the benefit here is not without some peril. The study should push us to personalize decisions with each of our patients and reach decisions based on their preferences and goals. The analysis of the trials sends a strong message that reflexively recommending aspirin to anyone over 50 cannot be justified by evidence that shows that the benefit exceeds the risks by a wide margin.”
Here is Sanjay Kaul’s take on the study:
“The results of this meta-analysis challenge the current AHA, ADA, ASA and USPSTF guidelines that recommend routine use of aspirin for primary prevention of heart disease (for men) and for stroke (for women) in individuals above a moderate level of risk of CHD—10-year CHD risk of >6-10%—(recently refined to >3-12% by USPSTF in its 2009 Update) and without contraindication to aspirin therapy. Interestingly, these data appear to justify the FDA’s stance on this issue. FDA has not approved aspirin therapy for primary prevention of CV disease in either men or women.
“Another important issue addressed by this meta-analysis relates to the gender-specific differences in treatment effect. A previous meta-analysis demonstrated that aspirin treatment protects women from stroke while men are protected from MI. However, a careful examination reveals that the stroke benefit in women was driven by the results of the Women’s Health Study (WHS) where the primary composite endpoint of cardiovascular death, nonfatal MI or nonfatal stroke failed to reach a statistical verdict. However, stroke incidence (a secondary endpoint) was significantly reduced. In such cases, any favorable secondary endpoint analysis should be deemed to be hypothesis generating and should not be used to formulate policy or guide clinical practice.
“Finally, I concur with the conclusions drawn by the authors that the decision to take aspirin for primary or secondary prevention should be individualized and predicated on a full accounting of its benefit-risk-cost assessment.”
Here is the press release from the Lancet:
ASPIRIN IN PRIMARY PREVENTION: REDUCES HEART ATTACKS, BUT INCREASES BLEEDS—SO NET VALUE UNCERTAIN
Use of aspirin by people with no history of relevant disease (primary prevention) reduces non-fatal heart attacks by around a fifth—but it also increases the risk of internal bleeding by around a third. Thus its long-term use in this population is of uncertain net benefit since these benefits and risks could cancel each other out. For secondary prevention (among those who already have occlusive vascular disease), aspirin’s benefits generally outweigh its small risks. The findings are discussed in an Article published in this week’s edition of The Lancet.
In this UK Medical Research Council funded study, Professor Colin Baigent, Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), University of Oxford, UK, and colleagues did an individual patient meta-analysis of serious vascular events (heart attack, stroke, or vascular death) and major bleeds in six primary prevention trials, involving 95,000 people at low-average risk, and 16 secondary prevention trials, involving 17,000 people at high risk. The studies compared long-term aspirin use with control.
The researchers found that in the primary prevention trials, aspirin reduced the already small risk of serious vascular events (stroke, heart attack, vascular death) by 12%, mainly due to the reduction in non-fatal heart attack mentioned above. There was no significant difference in stroke or in vascular mortality, but the small risk of internal bleeds increased by around a third in those given aspirin. In the secondary prevention studies, where people had already had a stroke or heart attack and were at substantial risk of recurrence, aspirin reduced the risk of serious vascular events by about a fifth, and this benefit clearly outweighed any small extra risk of bleeding. In both sets of trials, the proportional reductions in vascular events were similar for men and women.
The authors conclude: “The currently available trial results…do not seem to justify general guidelines advocating the routine use of aspirin in all healthy individuals above a moderate level of risk for coronary heart disease.”
Professor Baigent adds*: “Drug safety really matters when making recommendations for tens of millions of healthy people. We don’t have good evidence that, for healthy people, the benefits of long-term aspirin exceed the risks by an appropriate margin. If effectiveness is uncertain, then cost-effectiveness calculations are irrelevant.”
In an accompanying Comment, Professor Ale Algra and Dr Jacoba P Greving, University Medical Centre Utrecht, Utrecht, Netherlands, use a cost-effectiveness model to create a table** showing which populations might or might not benefit from aspirin in primary prevention — which shows that, in most cases, it is not justified. They conclude: “Patients might not wish to be medicalised —such considerations are important in the decision to take aspirin or not. Whether statins should be preferred above aspirin is a different and difficult question that needs careful consideration too. Apart from drug treatment, one must not forget the importance of lifestyle changes, such as cessation of smoking, healthy diet, and regular exercise.”