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Aspirin fails to improve CV outcomes, raises hemorrhage risk in older adults
Among older adults, low-dose aspirin did not reduce CVD risk vs. placebo and conferred an increase in risk for major hemorrhage, according to results of the ASPREE trial.
ASPREE is the third major aspirin trial to report primary prevention results recently. As Cardiology Today previously reported at the European Society of Cardiology Congress, in the ASCEND trial of patients with diabetes, aspirin lowered risk for vascular events but increased bleeding risk, and in the ARRIVE trial of participants without diabetes and at moderate risk, aspirin did not significantly reduce initial vascular events vs. placebo.
For ASPREE, primarily funded by the NIH, the researchers enrolled 19,114 patients from the United States and Australia aged at least 70 years ( 65 years in U.S. patients with black race or Hispanic ethnicity) without CVD, dementia and disability at baseline. All participants (44% men; 50% aged 74 years) were randomly assigned 100 mg per day enteric-coated aspirin or placebo.
The endpoints of interest included major hemorrhage and CVD, defined as fatal CHD, nonfatal MI, fatal or nonfatal stroke or HF hospitalization. Median follow-up was 4.7 years.
No difference in CVD events
During the study period, CVD events were similar between the aspirin group (10.7 events per 1,000 patient-years) and the placebo group (11.3 events per 1,000 patient-years; HR = 0.95; 95% CI, 0.83-1.08), John J. McNeil, MB, BS, PhD, from the department of epidemiology and preventive medicine at Monash University, Melbourne, Australia, and colleagues wrote in The New England Journal of Medicine.
Major hemorrhage occurred more often in the aspirin group (8.6 events per 1,000 person-years vs. 6.2 events per 1,000 person-years; HR = 1.38; 95% CI, 1.18-1.62), according to the researchers.
Low event rates
“On the basis of the results of previous trials, it was anticipated that benefits of aspirin treatment might arise from a reduction in the rate of cardiovascular events,” McNeil and colleagues wrote. “However, in this trial, the rate of ... cardiovascular disease (a composite that accounted for all cardiovascular events, including stroke due to intracranial hemorrhage and hospital admission for cardiac failure) was not significantly lower with low-dose aspirin than with placebo.”
Event rates being lower than expected may have played a role in the findings, McNeil and colleagues wrote.
“In the trial protocol, the anticipated rate was 22.4 events per 1,000 person-years,” they wrote. “The observed rate was approximately half this estimate, most likely reflecting the relatively good health of the participant population at recruitment and the declining rate of cardiovascular disease in the two countries over time and across all age groups.”
The CVD results comprised one of three papers published in NEJM about findings from ASPREE. In one paper, the overall primary outcome of death, dementia or persistent physical disability was almost identical between the aspirin and placebo groups. In another, all-cause mortality was higher in the aspirin group, driven by cancer-related deaths. – by Erik Swain
Disclosures: The study was funded by the NIH’s National Institute on Aging and National Cancer Institute, the National Health and Medical Research Council of Australia, Monash University and the Victorian Cancer Agency. McNeil reports nonfinancial support from Bayer AG during the conduct of the study. Please see the study for all other authors’ relevant financial disclosures.
Perspective
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The primary take-home message is that for patients who are 70 years or older, the risks of starting aspirin are likely to outweigh the benefits. Available evidence does not support initiation of aspirin for primary prevention of CVD among patients in these older age groups. ASPREE showed no improvement in the primary endpoint of disability-free survival and no significant reduction in CVD events. On the risk side, there was a significant increase in clinically significant bleeding events and a significant 14% increase in all-cause mortality due largely to an excess risk of cancer deaths.
The ASPREE, ARRIVE and ASCEND trials do not challenge or invalidate the 2016 U.S. Preventive Services Task Force (USPSTF) guidelines for aspirin use in primary prevention. Those guidelines recommend consideration of aspirin for patients ages 50-69 with a 10-year atherosclerotic CVD risk score of at least 10%, no excess risk of bleeding or contraindications to aspirin use, expected survival of at least 10 years, and patient willingness to take aspirin. The USPSTF gave a grade B recommendation (moderate certainty of net benefit) for low-dose aspirin for adults aged 50 to 59 years who meet these criteria and a grade C recommendation (not routinely recommended, individualize the decision) for those aged 60 to 69 years who meet these criteria. They considered the evidence to be insufficient (grade I) for adults younger than 50 years or age 70 years or older. Now, ASPREE makes it clear that the risks of starting aspirin among adults ages 70 and older are likely to outweigh the benefits; thus, the I (insufficient evidence) grade is likely to be changed soon to a D grade (recommend against use). Very few patients above age 70 would be appropriate candidates for starting aspirin, especially because the risks for all-cause mortality and deaths from cancer were increased, and long-term use would be required to see benefits for colorectal cancer prevention.
Regarding the other USPSTF recommendations, neither ARRIVE nor ASCEND challenge their validity. The ARRIVE population did not have high CV risk; it was more of a moderate-risk population and many of the participants would not have qualified for aspirin under the USPSTF recommendations. The ASCEND population had diabetes and the atherosclerotic CVD risk score was not specifically factored in, so that trial would not necessarily cast doubt on the USPSTF guidelines. As mentioned, the ASPREE trial provides further evidence against initiation of aspirin after age 70. However, if someone is in their 50s or 60s, has an atherosclerotic CVD risk score of 10% or higher and is doing well on aspirin, they may be a candidate for continuing aspirin past age 70. It remains unclear when a patient who started aspirin for primary prevention before age 60 or 70 should stop taking it. This issue requires individualized decision making and will benefit from further study.
Balancing the benefits and risks of aspirin is a challenge for clinicians. The free Aspirin-Guide mobile app is a clinical decision support tool that has been used by tens of thousands of clinicians to help weigh CVD benefits against bleeding risks. The app helps clinicians calculate the 10-year atherosclerotic CVD risk score, the bleeding risk score, and the number needed to treat vs. the number needed to harm, to help decide if a patient is a good candidate for aspirin. It’s based on the USPSTF guidelines, which are not refuted by these new trials, other than the reinforcement that aspirin should generally not be started after the age of 70 for the primary prevention of CVD.
Decisions about aspirin are optimal times for shared decision-making with patients. Active participation and engagement of patients in the decision-making process is very important. Many patients will not want to take an additional medication, are not likely to be compliant for 10 years, and may have other reasons to avoid aspirin, while other patients will be good candidates, very open to the decision, and are likely to be compliant. As we noted in a recent commentary in JAMA (Mora S, et al. JAMA. 2016;doi:10.1001/jama.2016.8362), decisions about aspirin use in primary prevention require individualized decision making and active engagement of the patient.