Aspirin in Older Adults

Abstract

In the treatment or secondary prevention of cardiovascular disease (CVD), there is general consensus that the absolute benefits of aspirin far outweigh the absolute risks. Despite evidence from randomized trials and their meta-analyses, older adults, defined as aged 65 years or older, are less likely to be prescribed aspirin than their middle-aged counterparts. In primary prevention, the optimal utilization of aspirin is widely debated. There is insufficient randomized evidence among apparently healthy participants at moderate to high risk of a first CVD event, so general guidelines seem premature. Among older adults, randomized data are even more sparse but trials are ongoing. Further, older adults commonly take multiple medications due to comorbidities, which may increase deleterious interactions and side effects. Older adults have higher risks of occlusive events as well as bleeding. All these considerations support the need for individual clinical judgments in prescribing aspirin in the context of therapeutic lifestyle changes and other adjunctive drug therapies. These include statins for lipids and usually multiple drugs to achieve control of high blood pressure. As regards aspirin, the clinician should weigh the absolute benefit on occlusion against the absolute risk of bleeding. These issues should be considered with each patient to facilitate an informed and person-centered individual clinical judgment. The use of aspirin in primary prevention is particularly attractive because the drug is generally over the counter and, for developing countries where CVD is becoming the leading cause of death, is extremely inexpensive. The more widespread use of aspirin in older adults with prior CVD will confer net benefits to risks and even larger net benefits to costs in the United States as well as other developed and developing countries. In primary prevention among older adults, individual clinical judgments should be made by the health-care professional and each of his or her patients.

Aspirin in Secondary Prevention in Older Adults

In secondary prevention or treatment of cardiovascular disease (CVD), aspirin confers net benefits among patients experiencing an acute myocardial infarction (MI). ¹ For example, among patients having acute MI, aspirin given immediately and continued for 35 days produces statistically significant and clinically important reductions in vascular death by 23%, MI by 49%, stroke by 46%, and all occlusions by 28%. These landmark findings derive the Second International Study of Infarct Survival 2, which randomized 17 187 patients within 24 hours of onset of symptoms of acute MI to 162.5 mg aspirin or placebo daily for 35 days. Although there was no upper age limit, a relatively small proportion of patients were older than 75 years of age. Nonetheless, aspirin conferred similar relative benefits of occlusive events among older adults than their middle-aged counterparts. Since older adults have higher absolute risks of occlusive events, they also experience greater absolute benefits.

Among survivors of a wide range of occlusive vascular events including patients with prior MI, coronary artery bypass grafting, angioplasty, stable angina, atrial fibrillation, occlusive stroke, transient ischemic attacks, and peripheral arterial disease, the absolute benefits of aspirin on subsequent occlusive events are also far greater than the absolute risks of bleeding. These findings are based on a meta-analysis of 287 randomized trials which included 212 000 high-risk patients. ² There were 135 000 patients assigned at random to antiplatelet therapy, principally aspirin, versus control and 77 000 assigned at random to different antiplatelet regimens. Antiplatelet therapy, principally with aspirin, reduced subsequent occlusive vascular events by about 25%, nonfatal MI by about 33%, nonfatal stroke by about 25%, and vascular deaths by about 17%. In these high-risk patients, the absolute reductions in occlusive events were 10- to 20-fold higher than the absolute risk of a major bleed. In direct and indirect comparisons, 75 to 150 mg daily aspirin was at least as effective as higher daily doses and produced less major bleeding.

These statistically significant and clinically important reductions included patients up to 85 years and showed no cogent evidence of effect modification by age. Nonetheless, older adults are less likely to be prescribed aspirin during or after a CVD event. For example, among elderly patients hospitalized with acute MI and no contraindications, aspirin was prescribed at discharge to 76%, a value much lower than that achieved of over 90% among comparable patients in middle age. ³

Aspirin in Primary Prevention in Older Adults

In primary prevention of CVD, the optimal utilization of aspirin is widely debated. There is insufficient randomized evidence among apparently healthy participants at moderate to high risk of a first CVD event. Thus, in primary prevention, general guidelines seem premature for all ages, especially older adults, for whom randomized data are even more sparse than in middle-aged adults. Further, older adults commonly take multiple medications due to comorbidities, which may increase the likelihood of deleterious interactions and side effects. Finally, older adults have higher risks of occlusive events as well as bleeding. ⁴

In a comprehensive meta-analysis of 6 major primary trials including over 95 000 men and women, the daily doses ranged from 75 to 500 mg. ⁴ There were statistically significant reductions of 18% for major coronary events, 14% for stroke, and 12% for all occlusive events. As regards risks, there was a 30% increase in major bleeding. These relative benefits and risks were similar in men and women as well as in middle-aged and older adults. Further, while older adults were at high risk of occlusive events, they also appeared to be at higher risks of major bleeding. Finally, those at higher risks of complications from aspirin included participants taking nonsteroidal anti-inflammatory drugs or with a history of gastrointestinal disorders and bleeding. In addition, even apparently healthy older participants are at higher risks of falls and their complications including contusions and serious bleeding. In these analyses, the absolute benefits of aspirin exceeded the absolute risks only for the subgroup of apparently healthy participants with a 10-year risk of a first coronary event of 10% or greater. In this meta-analysis, only about 10% of participants in the major primary prevention trials had a 10-year risk of a first coronary event of 10% or greater, with an average of <5%. Thus, a major problem for the health-care professional derives from the fact that the absolute benefits are so much lower for apparently healthy people but the absolute risks are not. As a consequence, in primary prevention participants, it is far more difficult to judge whether the absolute benefit of aspirin outweighs the absolute risk.

Need for Individual Clinical Judgments in Primary Prevention

In primary prevention, the current totality of evidence is incomplete. ⁵ We concur with statements from several regulatory authorities in Europe and the United States that any general guidelines for aspirin in primary prevention are premature. ⁶ Investigators throughout the world are conducting several randomized trials of aspirin in apparently healthy individuals at moderate to high risk of a first coronary event, which, of necessity, includes older adults. ^5,6,7 For example, the Aspirin in Reducing Events in the Elderly trial has met the recruitment target of 19 000 apparently healthy men and women at least 70 years of age. The Aspirin to Reduce Risk of Initial Vascular Events trial has randomized over 12 000 participants with a 10-year risk of a first coronary event of 15% or greater. To do so, they are restricting enrollment to men ≥55 years old and women ≥60 years old, both of whom must have 2 or more risk factors. Two randomized trials are evaluating apparently healthy men and women with diabetes mellitus. These are A Study of Cardiovascular Events in Diabetes and the Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trials in Diabetes trial. If all these trials achieve adequate numbers of randomized participants as well as high levels of compliance and follow-up, they will add important and relevant information to the currently incomplete evidence on aspirin in primary prevention. Meanwhile, we should not let the perfect be the enemy of the possible, so any conclusion about whether to prescribe aspirin should be made as an individual clinical judgment by the health-care professional and each of his or her patients. We believe that any decision to take a drug long term, especially among older adults, should be based on a shared decision-making process, involving the health-care professional and each of his or her patients and their families. The individual clinical judgment should be based on the totality of evidence as well as the patient’s goals of care. Thus, any decision to prescribe long-term aspirin for older adults should include, but not be limited to, weighing the absolute risk of a first occlusive vascular event against the absolute risk of a major extracranial bleed. It should be noted that there are many risk algorithms, but factors not included may include obesity, physical inactivity, and family history. In addition, the benefits of aspirin and statins are, at least, additive. ⁸ Finally, a meta-analysis of 5 randomized trials showed that aspirin reduces risks of colorectal cancer. ⁹ The absolute risk of colorectal cancer alone may be too low to warrant aspirin prophylaxis, but a positive family history may alter this judgment.

As a general rule, guidelines should provide guidance to clinicians and not replace astute clinical judgments. ^5,6,7 With respect to aspirin in primary prevention, more evidence is needed. Nonetheless, it is interesting to note that the US Preventive Services Task Force also estimates that apparently healthy men and women should be considered as possible candidates for aspirin if their 10-year risk of a first coronary event is at least 10%.

Conclusions

Longer life expectancies in the United States and increasing rates of CVD in developed and developing countries indicate the need for more widespread therapeutic lifestyle changes as well as adjunctive drug therapies of proven net benefit. These include statins for lipids and usually multiple drug therapies to achieve control of high blood pressure. ^{10 –12}

In secondary prevention, the more widespread use of aspirin in older adults with prior CVD will confer net benefits to risks and even larger net benefits to costs in the United States as well as other developed and developing countries.

In primary prevention, the clinician should weigh the absolute benefit on occlusive events against the absolute risk of bleeding. This individual clinical judgment may also consider the benefit of aspirin on the prevention of colon polyps and colorectal cancer. The individual health-care provider should consider these issues in collaboration with each of his or her patients. With respect to older adults, modern geriatric care emphasizes astute clinical judgment and person-centered care in collaboration with patients to make individualized decisions based on the available evidence, as well as patient goals and preferences. The use of aspirin in primary prevention of CVD is particularly attractive, because the drug is generally over the counter and, for developing countries where CVD is rapidly becoming the leading cause of death, ¹⁰ is extremely inexpensive. ¹¹ In primary prevention among older adults, until further randomized evidence becomes available, individual clinical judgments should be made by the health-care professional in collaboration with each of his or her patients. ^{10 –12}