Robert M. Zimbroff, MD, Gina Ayers, PharmD, BCPS, BCGP and Kenneth Koncilja, MD

Cleveland Clinic Journal of Medicine November 2021, 88 (11) 632-634; DOI: https://doi.org/10.3949/ccjm.88a.21024

No. Recent evidence shows that the harms of aspirin use for the primary prevention of cardiovascular disease usually outweigh the benefits for patients age 70 and older.

An updated draft of the United States Preventive Services Task Force (USPSTF) recommendations for aspirin use was released for public comment on October 12, 2021.^1,2 These guidelines have a grade C recommendation for initiating low-dose aspirin for primary prevention of cardiovascular disease in patients ages 40 to 59 with a 10% or greater 10-year risk of cardiovascular disease. (Grade C: Recommends use based on professional judgment and patient preferences. There is at least moderate certainty that the net benefit is small.) These guidelines offer a grade D recommendation for initiating low-dose aspirin for primary prevention of cardiovascular disease in adults age 60 and older. (Grade D: Recommends against. There is at least moderate certainty of no net benefit or that harms outweigh benefit). This guidance is a change from their 2016 recommendation, which was equivocal on adults ages 60 to 69 and avoided a recommendation for adults age 70 and older, citing insufficient evidence.^3,4 Trials reviewed in this article were included in these updated draft recommendations, which are still open for comment at the time of this writing.

In 2018, results from 3 large double-blind, randomized, placebo-controlled trials offered insight into how to approach aspirin use for primary prevention in older adults. These trials—Aspirin in Reducing Events in the Elderly (ASPREE),^5,6 Aspirin to Reduce Risk of Initial Vascular Events (ARRIVE),⁷ and Aspirin for Primary Prevention in Persons With Diabetes Mellitus (ASCEND)⁸—provide substantial data to fill knowledge gaps on how to consider prescribing or de-prescribing aspirin for older patients.

WHAT DID THE TRIALS FIND?

The ASPREE trial

This trial enrolled 19,114 community-dwelling older adult patients at least 70 years old, or at least 65 years old for Black and Hispanic patients, without evidence of cardiovascular disease (overall median age was 74).^5,6 During a median follow-up of 4.7 years, researchers found that 100 mg/day of aspirin provided no benefit in preventing nonfatal cardiovascular events or death, or in increasing disability-free survival. Aspirin use increased the risk of clinically significant, nonfatal major hemorrhage, defined as a composite measure of intracranial and upper or lower gastrointestinal bleeding that required transfusion, hospitalization, or surgical intervention, or that prolonged hospitalization. Unexpectedly, the aspirin cohort had higher all-cause mortality, attributed to increased cancer-related mortality (including a significant increase in colorectal cancer-related death in aspirin users). Mortality from major bleeding events, including hemorrhage or hemorrhagic stroke, was no different between groups.^5,6

The ARRIVE trial

This trial enrolled 12,546 patients age 55 and older for men and age 60 and older for women with moderate cardiovascular disease risk assessed by the presence of risk factors including current tobacco use, low levels of high-density lipoprotein cholesterol, elevated systolic blood pressure (> 140 mm Hg), prescriptions for antihypertensive medications, or positive family history of cardiovascular disease.⁷ The trial was focused on primary prevention, so investigators excluded participants with prior cardiovascular events or interventions (eg, stenting, angioplasty, bypass surgery). Patients with diabetes were also excluded. The intent-to-treat analysis showed no significant benefit for aspirin use of 100 mg/day during the median 5-year followup. A subgroup analysis showed no benefit for patients age 65 and older. As in earlier studies,⁹ the aspirin-receiving cohort had an increased risk of gastrointestinal bleeding.

The ASCEND trial

This trial enrolled 15,480 participants with diabetes but without known cardiovascular disease; nearly one-quarter of participants enrolled were at least 70 years of age.⁸ Although 100 mg/day of aspirin provided an overall benefit in reducing first vascular events, a subgroup analysis revealed no benefit for patients age 70 and older. Aspirin use was associated with a higher risk of major bleeding events, defined as bleeding requiring transfusion, hospitalization, surgical intervention, or that prolonged hospitalization, required intensive care unit admittance, or caused death. This risk was significant for patients age 60 and older but was not significant for patients under age 60.⁸

HOW DID MEDICAL SOCIETIES REACT?

In light of these findings, the American College of Cardiology (ACC) updated its practice guidelines, published in September 2019, to state that low-dose aspirin should not be administered on a routine basis for the primary prevention of atherosclerotic cardiovascular disease in adults over age 70.¹⁰ The American Diabetes Association (ADA), in its practice guidelines published in January 2021, similarly recommended that for patients over age 70 (with or without diabetes), aspirin use appears to have greater risk than benefit and thus is not recommended in these patients.¹¹

Complementary interventions aimed at reducing the risk of cardiovascular events—statins for hyperlipidemia, improved antihypertensive medications, and aggressive anti-smoking campaigns—may further reduce the utility of aspirin for primary prevention. Nevertheless, data from the National Health and Nutrition Examination Survey (2011-2018) showed that aspirin use for primary prevention significantly increased as patients age, from 24% in those ages 50 to 54 to 45.3% in those age 75 and older.¹²

WHAT ABOUT ASPIRIN USE FOR COLORECTAL CANCER?

In addition, there is increasingly clear evidence supporting discontinuation of aspirin use in older adults for colorectal cancer prevention. The USPSTF had previously made a grade B recommendation for low-dose aspirin in adults ages 50 to 59 in part because of evidence supporting reduced colorectal cancer incidence after 5 to 10 years of use.^3,4 A more recent pooled analysis of data on 94,540 participants age 70 and older from both the longitudinal Nurses’ Health Study and the Health Professionals Follow-up Study found that aspirin use was associated with a lower incidence of colorectal cancer after age 70 for patients who initiated aspirin before age 70 with at least 5 years of use.¹³ Initiating aspirin after age 70 was not associated with reduced colorectal cancer incidence. The ASPREE investigators reported increased cancer-associated mortality risk in the aspirin-use cohort (including higher colorectal cancer mortality); however, they noted that this result was unexpected in the context of other well-designed aspirin trials and should be interpreted cautiously.¹⁴

THE BOTTOM LINE

The proposed updates to its 2016 guidance for aspirin use for primary prevention in adults age 60 and older^1,2 put the USPSTF recommendations in line with those of the ACC and ADA,^9,11 which both previously incorporated evidence from the trials discussed above into their recommendations against aspirin use for primary prevention in older adults.

Our clinical recommendation is in line with the USPSTF’s proposed update: the risks outweigh the benefits for aspirin in older adults. Providers, in conjunction with patients, should de-prescribe aspirin as able.

DISCLOSURES

The authors report no relevant financial relationships which, in the context of their contributions, could be perceived as a potential conflict of interest.

• Copyright © 2021 The Cleveland Clinic Foundation. All Rights Reserved.

REFERENCES – click on article link above

Daily Low-Dose Aspirin, Diabetes, and Age—Still Looking for a Balance

Wilson D. Pace, MD¹ – June 21, 2021

Author Affiliations Article Information

JAMA Netw Open. 2021;4(6):e2112875. doi:10.1001/jamanetworkopen.2021.12875

According to federal surveys, aspirin is one of the most commonly taken medications in the US, with over 20% of people older than 40 years using low-dose aspirin daily.¹ In JAMA Network Open, Liu and colleagues² explore regular aspirin use in individuals older than 60 years, analyzing a number of variables related to the benefits and risks and how they relate to daily aspirin use. Their analysis of the National Health and Nutrition Examination Survey data from 2011 to 2018 highlights that aspirin usage in individuals with known cardiovascular disease (CVD) is in the 70% range, which is similar to previous estimates.³ Given that other antiplatelet medications were not included, nor were individuals with high bleeding risk accounted for, this percentage may be approaching a logical ceiling in the population included in this analysis. The benefit-to-risk ratio of daily low-dose aspirin is high in individuals with known CVD disease; thus, continued use beyond age 70 years in most individuals is clinically logical.

However, the analysis by Liu et al² also points out that a large percentage of individuals 70 years and older take daily aspirin in the absence of known CVD. The good news is that, generally, daily aspirin use is directly proportional to overall CVD risk, with individuals who have few risk factors for CVD being the least likely to take daily aspirin compared with those with known CVD disease being the most likely use aspirin. The concern is that there is a considerable percentage of individuals at low risk for CVD who are taking aspirin therapy across all age groups. Many individuals included in this analysis may have higher risks for adverse events than for improved health outcomes.

Dating back to the 1970s, the use of aspirin for the primary prevention of acute coronary events has been considered and studied. In the past decade, aspirin use for primary prevention has been promoted by quality indicator developers, advocacy groups, and specialty societies. Yet, despite ongoing study, until recently, data indicating a clear-cut benefit of low-dose aspirin for primary prevention have been lacking. In 2016, the US Preventive Services Task Force (USPSTF) released a B recommendation (ie, at least moderate certainty for a moderate benefit) for aspirin use for primary prevention of CVD and colorectal cancer for individuals aged 50 to 59 years.⁴ This assessment was based heavily on 3 commissioned evidence reviews, including a meta-analysis and microsimulations, as individual trials failed to demonstrate a positive effect. For the age group older than 70 years, the USPSTF indicated that there was insufficient evidence to judge benefits vs risks.

Three new studies examining daily aspirin use and primary prevention outcomes have been published since the USPSTF statement.^5–7 Combined, these studies enrolled more than 47 000 people with greater than 63% of the participants aged older than 60 years and at least 50% older than 70 years, making the results apropos to the Liu article.² Two of the studies had no positive outcomes,^5,6 either primary or secondary, and thus further support the questionable extensive use of aspirin for primary prevention in those 70 years and older. The third study, the ASCEND (A Study of Cardiovascular Events in Diabetes) trial,⁷ specifically enrolled individuals with type 1 or type 2 diabetes and showed a significant reduction in cardiovascular events over a period of 7.4 years (percentage of individuals, intervention vs control, 8.5% vs 9.6%; 95% CI, 0.79-0.97). Major bleeding events, a well-known adverse event with aspirin therapy at any dose, also increased as expected. Tallying the number of serious vascular events or revascularization procedures avoided and subtracting from them the number of major bleeding events caused, the results indicate that 0.34 events would be avoided per 1000 person years in the highest cardiovascular risk group, decreasing as risk decreases. Despite the overall positive outcomes, the authors concluded that it was not clear that the benefits of aspirin therapy in people at low risk for CVD outweighed the harms.⁷

None of the 3 studies^5–7 demonstrated an improvement in mortality, either all cause or cardiovascular (depending on the study), with one, the ASPREE (Aspirin in Reducing Events in the Elderly) study,⁵ having higher all-cause mortality in the aspirin group. The increased deaths were primarily cancer related and downplayed by the authors, though examination of a large number of demographic and risk categories indicates that randomization appeared to have worked well, making an anomaly such as this concerning. When these 3 new studies^5–7 are considered, along with the more than 95 000 individuals included in the reviews conducted for the USPSTF, the use of aspirin for the primary prevention of CVD or to lower all-cause mortality for individuals older than 70 years becomes even harder to justify. The study by Liu et al² indicated that more than 20% of individuals in the analysis with low cardiovascular risk use daily aspirin. This percentage rises to greater than 50% of the individuals older than 80 years. This rate of aspirin use is poorly justified by current evidence and would seem likely to be causing more harm than good. That said, clinicians are left with a conundrum, because the USPSTF simulations indicate that the overall benefit from low-dose aspirin increases over time, particularly with respect to cancer prevention. Furthermore, most individuals older than 70 years using daily aspirin are not newly initiating therapy but continuing therapy started at a younger age. Stopping a therapy on which an individual appears to be doing well can be a much harder decision for both patient and clinician than not starting the treatment in the first place. Despite the concern that stopping medication may lead to worse outcomes, low-dose aspirin therapy, like all medications used by older individuals, should be regularly reviewed, and the ongoing safety and need for use should be discussed. With the addition of 3 newer studies^5–7 that continue to question the efficacy of low-dose aspirin for primary prevention in older adults, this conversation has more immediacy. Only through careful, ongoing assessments can physicians make sure they are following what many consider to be the most important ethical tenet of clinical care—primum non nocere—first, do no harm.

Article Information

Published: June 21, 2021. doi:10.1001/jamanetworkopen.2021.12875

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Pace WD. JAMA Network Open.

Corresponding Author: Wilson D. Pace, MD, Chief Medical Officer, DARTNet Institute, 12635 E Montview Blvd, Mail Box 3, Aurora, CO 80045 (wilson.pace@dartnet.info).

Conflict of Interest Disclosures: None reported.

References – click on link above