Introduction
The leading cause of death in the United States is cardiovascular disease (Sturgeon et al., 2019). Not only is the number of individuals with cardiovascular disease increasing but also the cost associated with cardiovascular disease in the United States is increasing as well. From 1996 to 2016, the annual spending in the United States on cardiovascular disease rose from $212 billion to $320 billion (Birger et al., 2021). The annual cost of cardiovascular disease is predicted to increase because people are living longer and the population is increasing.
Aspirin, also known as acetylsalicylic acid, is a commonly used medication for the treatment of cardiovascular disease (Mainous et al., 2014). Aspirin is in the class of nonsteroidal anti-inflammatory drugs, which help it provide anti-inflammatory properties and pain relief for patients. In addition, aspirin also blocks cyclooxygenase, thereby providing an antithrombotic effect (Cadavid, 2017). Aspirin's antithrombotic effects make it useful for preventing future heart attacks and strokes in patients. Although aspirin is a well-established therapy that has been used for many years in millions of patients, it is not risk free. Because of the fact that aspirin has antithrombotic qualities, it can also increase the risk of bleeding in patients, which often leads to controversy over its benefit.
Patients who already have cardiovascular disease are often started on daily low-dose aspirin as secondary prevention because they are at high risk of suffering from future cardiovascular events. Low-dose daily aspirin, between 75 and 100 mg daily, is shown to significantly reduce future cardiovascular events in patients who have already have a cardiovascular disease (Ittaman et al., 2014). Although the benefits of aspirin more clearly outweigh the risks in patients who have a history of cardiovascular disease, aspirin is more controversial as primary prevention in patients who are at risk of developing cardiovascular disease (Ittaman et al., 2014). The goal of primary prevention is to prevent disease from occurring (Kisling & Das, 2021). Currently, there are no clear and consistent recommendations for the use of aspirin for the primary prevention of cardiovascular disease.
Providers often decide to prescribe low-dose aspirin on a case-by-case basis. The recommendation by the US Preventive Service Task Force (USPSTF) suggests that for adults 40-59 years old with a 10% or greater risk of cardiovascular disease, the decision for using aspirin as primary prevention should be made on an individual basis. For adults 60 years and older, the USPSTF recommends against initiating low-dose aspirin for cardiovascular prevention (USPSTF, 2022). Despite the lack of strong evidence on aspirin's use as primary prevention, approximately 9.9 million older American adults are taking aspirin as primary prevention for cardiovascular disease (Liu et al., 2021).
This article aims to answer the following question, "Do adults without a history of cardiovascular disease benefit from taking daily low-dose aspirin for the primary prevention of cardiovascular disease?"
Methods
A literature search was performed using PubMed, CINAHL, Scopus, and Ovid databases. The search terms used in PubMed and Ovid included "low-dose aspirin" AND "primary prevention" AND "cardiovascular disease." In CINAHL and Scopus, additional terms used included ("randomized control trial" OR "meta analysis" OR "clinical trial") because they did not have filters for these parameters. Initial results led to 151 articles, 25 articles, and 157 articles, 31 articles on PubMed, CINAHL, Scopus, and Ovid, respectively. Next, on PubMed, the filters of "randomized control trials," "clinical trials," and "meta analysis" were added, decreasing the PubMed results to 39 articles. Next, a filter for articles published in the past 10 years (2012-2022) was added, leading to 13 articles, 10 articles, 63 articles, and 25 articles on PubMed, CINAHL, Scopus, and Ovid, respectively. After that, an English filter was added bringing down the articles to 13 articles on PubMed, 10 articles on CINAHL, 60 articles on Scopus, and 25 articles on Ovid. All together, after narrowing down the search results, there were 67 nonduplicate articles that were reviewed.
Abstracts were reviewed and included if they studied the impact of daily low-dose aspirin as primary prevention on cardiovascular disease. Articles were excluded if they did not produce any of their own data (n = 14) and if they did not specifically look at cardiovascular outcomes (n = 39). Articles that only looked at patients with diabetes and eliminated anyone who did not have diabetes were excluded (n = 11). If an article had a primary or secondary outcome looking at cardiovascular disease in relation to using low-dose aspirin as primary prevention, the article was included. After thoroughly reviewing all the 67 articles based on the criteria mentioned, four articles were included. See attached PRISMA diagram below in Figure 1.
After the literature search, the reviewer examined the data and analyzed the quality of evidence. Of the four articles included, three were randomized controlled trials (Gaziano et al., 2018; Ikeda et al., 2014; McNeil et al., 2018), and one was a retrospective cohort study (Zhao et al., 2020). The CONSORT guideline was used to evaluate the evidence for the randomized control trials, and the STROBE guideline was used to evaluate the evidence of the retrospective cohort study. The results from this analysis were organized into a Table of Evidence, which can be found in Appendix (Supplemental Digital Content 1, http://links.lww.com/JAANP/A172).
Results
Patient populations
The data collection for the four articles occurred between 2005 and 2017, and the articles themselves were published between 2014 and 2020. The studies were conducted worldwide. Only Gaziano et al. (2018) and McNeil et al. (2018) included participants from more than one country. McNeil et al. (2018) investigated participants in the United States and Australia, whereas Gaziano et al. (2018) investigated participants from Germany, Italy, Ireland, Portland, Spain, the United Kingdom, and the United States. Ikeda et al. (2014) only included participants from Japan, and Zhao et al. (2020) only included participants living in Northern Territory, Australia.
The trials all had relatively large sample sizes ranging from 8,167 to 19,114 individuals, with a total of 54,291 patients across all trials. Of all four studies, only Ikeda et al. (2014) included a power analysis to determine appropriate sample size. They assessed that including at least 10,000 participants would provide 80% power to establish whether aspirin could result in up to a 20% reduction of cardiovascular risk. Ikeda et al. (2014) met this appropriate sample size because they had 14,464 participants in their study.
Participants included in the three randomized control trials (Gaziano et al., 2018; Ikeda et al., 2014; McNeil et al., 2018) ranged from age 55 years with no upper age limit specified, except the study by Ikeda et al. (2014) stopped screening participants to be included at age 85 years. The retrospective cohort study by Zhao et al. (2020) included data from participants 18 years and older with no upper age limit specified. All studies had variations in their demographics including age, gender, and risk factors for cardiovascular disease. Two of the trials provided a mean age that ranged from 63 to 70 years (Gaziano et al., 2018; Ikeda et al., 2014). The other two trials provided a median age ranging from 42 to 74 years (McNeil et al., 2018; Zhao et al., 2020). The trial conducted by Gaziano et al. (2018) had a significant male dominant population comprising 79% of the participants, whereas the other three trials had males comprising closer to half of the participating population ranging from 42% to 48%. In addition, all four studies looked at the percentage of their samples that came in with pre-existing hypertension and some component of dyslipidemia. Among participants of all studies, rates of pre-existing hypertension ranged from 32% to 84%, and rates of pre-existing dyslipidemia ranged from 33% to 72%.
Eligibility for inclusion of the studies varied quite drastically, whereas exclusion criteria were fairly similar. As mentioned above, all the studies had a minimum age inclusion criteria ranging from 18 to 55 years, whereas only Zhao et al. (2020) listed a maximum inclusion age of 85 years. Both Gaziano et al. (2018) and Ikeda et al. (2014) required that patients had some cardiovascular risk factors including hypertension, dyslipidemia, smoking, or diabetes. On the other hand, in both Zhao et al. (2020) and McNeil et al. (2018), participants were not required to have any pre-existing cardiovascular risk factors. In fact, the study by McNeil et al. (2018) was aiming to examine healthy community-dwelling older adults. McNeil et al. (2018) required participants to be free from cardiovascular disease, atrial fibrillation, dementia, a significant physical disability, bleeding risk, anemia, or inability to take aspirin for any reason.
The participants investigated in Zhao et al. (2020) were also quite different from the other studies because this study aimed to examine the effects of daily low-dose aspirin on people living in remote Aboriginal communities in the Northern Territory of Australia. This study had a more specific patient population, the Aboriginal population, which is known to be at higher risk of diabetes, ischemic heart disease, and stroke. Given the fact that this population often experiences these conditions up to two decades earlier than average Australians, they have a significantly younger inclusion age in their study (age 18 years or older) compared with the other studies (Zhao et al., 2020).
Exclusion criteria for all four studies included a history of cardiovascular disease, a history of cerebrovascular disease, anticoagulation or antiplatelet medication before the trial, or high risk of bleeding. The three randomized control trials also excluded any participants who had atrial fibrillation or any type of sensitivity or allergy to aspirin.
Methodological differences
Although all four articles assessed low-dose aspirin as primary prevention for adults without cardiovascular disease, various methods were used to study and assess the relationship. McNeil et al. (2018) and Gaziano et al. (2018) were both multicenter randomized, double-blind, placebo-controlled clinical trials. Although the study by Ikeda et al. (2014) was also a multicenter randomized control trial, the study was open label and did not use placebo. Therefore, participants and providers knew whether the intervention was being given. The study by Zhao et al. (2020) was a retrospective cohort study design that collected and analyzed data from two Northern Territory Departments of Health centers in Australia.
All three of the randomized control trials used 100 mg of enteric-coated aspirin daily as the intervention. The participants in the control groups of McNeil et al. (2018) and Gaziano et al. (2018) were given a placebo pill to avoid bias; on the other hand, the participants in the control group of Ikeda et al. (2014) were not given any placebo or supplement. Because the study by Zhao et al. (2020) was a retrospective cohort study, they did not introduce an intervention. Rather, they looked back on data and compared outcomes of patients who were given 75-162 mg of aspirin a day versus patients who were not on any aspirin. Follow-up for participants in all four trials ranged between 4 and 5 years; the three randomized control trials listed a median follow-up time ranging from 4.7 to 5.02 years, and Zhao et al. (2020) listed a mean follow-up time of 4 years.
Although all the trials included had an endpoint assessing cardiovascular disease, some studies assessed this through their primary outcomes and others through their secondary outcomes. As bleeding is a major side effect of taking aspirin, all studies also looked at severe hemorrhage either as an outcome or as a safety endpoint. Gaziano et al. (2018) and Ikeda et al. (2014) listed their primary outcome to include death from cardiovascular causes, nonfatal stroke, and nonfatal myocardial infarction. Zhao et al. (2020) listed outcome measures to include cardiovascular death, incidence of cardiovascular events, and major bleeds. Only McNeil et al. (2018) had cardiovascular disease and major hemorrhage as a secondary endpoint, with a primary endpoint of death, dementia, or persistent physical disability.
Outcomes
Gaziano et al. (2018; p = .6), Ikeda at el. (2014; p = .54), McNeil et al. (2018; hazard ratio, 0.95; 95% confidence interval [CI], 0.83-1.08), and Zhao et al. (2020; p = .5) all found that taking daily low-dose aspirin as primary prevention does not significantly decrease the risk of cardiovascular death or from having a cardiovascular event overall. Although McNeil et al. (2018) did not include p values for cardiovascular outcomes, because the 95% CI crossed 1.00, the p value would be greater than .05 deeming it nonsignificant. Zhao et al. (2020) found low-dose daily aspirin was associated with a reduction in all-causes of death among Aboriginal people (p < .001). Although Ikeda et al. (2014) did not find aspirin to prevent cardiovascular death and events overall (p = .54), a secondary outcome showed that the aspirin group had a lowering of nonfatal myocardial infarction (p = .02) and transient ischemic attack (p = .04) when looking at these endpoints individually.
When looking at rates of hemorrhage, the three randomized control trials also showed a statistically significant increase in bleeding among the aspirin group versus the placebo group with p values of p = .0007, p = .004, and p < .001, respectively (Gaziano et al., 2018; Ikeda et al., 2014; McNeil et al., 2018). On the other hand, Zhao et al. (2020) did not find any statistically significant increase in hemorrhage rates among the aspirin group over the control group (p = .82).
Limitations
A limitation with all the four studies was that they all had lower observed cardiac events than expected in the general population. The studies could attribute this bias to a variety of reasons. McNeil et al. (2018) mentioned this phenomenon could be due to the fact that they chose to only include a healthy sample population. The small sample size in Zhao et al. (2020), which was further reduced by propensity score matching (PSM) and coarsened exact matching (CEM), could have contributed to the low number of observed events. Gaziano et al. (2018) mentioned that after the first year, follow-up with participants was only once a year and could have led to failure of participants to report cardiovascular events. Finally, the low incidence rate in the Ikeda et al. (2014) trial could be due to the fact that the participants were all Japanese who have a lower prevalence of smoking and lower body mass index compared with Western populations. Another important note is that lower rates of cardiovascular events and death in the trials could be due specifically to the patient's participation in these trials. The participants had more frequent and close follow-up with health care providers, which could have led to risk factors being addressed earlier than they would have been otherwise (Ikeda et al., 2014).
Another limitation to the four trials was adherence with the intervention and with the trial. The study by McNeil et al. (2018) notes about two thirds of participants were compliant with their assigned intervention by the end of the trial. The study by Gaziano et al. (2018) describes that 29% of their participants terminated their participation from the study prematurely mostly because of withdrawal, loss to follow-up, death, or other reasons. The study by Ikeda et al. (2014) reports that the aspirin group adherence dropped to 76% by the fifth year of follow-up, as well as up to 10% of participants in the nonaspirin group started taking aspirin. Finally, the study by Zhao et al. (2020) mentions a major limitation was that they were unable to account for adherence to aspirin because they were a retrospective cohort study. In addition, they reported that although they do not have data on adherence, medication adherence is reported to be low among the Aboriginal communities, and the overall nonadherence rate for medication within this community is up to 33% (Zhao et al., 2020). Lack of adherence to aspirin in the aspirin group or taking aspirin in the nonaspirin group could significantly affect the results of the studies and make finding associations between aspirin and cardiovascular events or death challenging. Future studies investigating aspirin's role in preventing cardiovascular disease and death should have distinct and constant methods for measuring adherence.
In addition, a limitation includes that the studies were conducted in several countries around the world with ranging ages and presence of various risk factors. Although having such a range in populations could be beneficial for studying aspirin use in diverse populations, it could also pose a limitation by overlooking specific factors in each population that would affect rates of cardiovascular disease and death. All the countries have different health care systems, diets, lifestyles, primary prevention efforts, and smoking rates. These are just a few factors that could directly influence a population's risk of cardiovascular disease and death, making it hard to generalize the findings from one of the studies to all populations.
The search process itself for the relevant articles could have posed bias. The Gaziano et al. (2018) study was only discovered through a reference of a different article that was eliminated (Rhee et al., 2021). The study may not have shown up in the search because of the bias of the specific filters or search terms being used. There could be other relevant studies such as the Gaziano et al. (2018) study, which were also never discovered because of a similar bias. In addition, there were several articles that investigated aspirin's effect on various outcomes; however, articles were eliminated if they did not specify cardiovascular outcomes.
Discussion
The main findings of this review is that the data do not support using daily low-dose aspirin as primary prevention for cardiovascular disease. All four studies found no statistically significant difference in overall cardiovascular disease and cardiovascular death rates among aspirin users. The studies mentioned that determining whether a patient with no history of cardiovascular disease should be started on low-dose daily aspirin should still be individualized because of lack of enough research. The current practice is to weigh each case individually and consider the specific aspects of the patient including age, bleeding risk, comorbidities, and cardiovascular risk factors.
The USPSTF recently came out with updated guidelines in April 2022 for aspirin's use as primary prevention for cardiovascular disease. Their guidelines are in line with the recommendations from the articles analyzed for this review. The newest USPSTF recommendations are as follows: adults aged 40-59 years who have a 10% or greater risk of developing cardiovascular disease, and are not at an increased risk of bleeding, should be started on aspirin on a case-by-case basis. Adults 60 years and older should not be started on low-dose aspirin as primary prevention for cardiovascular disease, with a grade D recommendation (USPSTF, 2022).
The USPSTF update mentions that adults between the ages of 40-59 years that could potentially qualify for aspirin, the evidence shows aspirin has a small net benefit with a grade C recommendation (USPSTF, 2022). Although the data on using aspirin as primary prevention for cardiovascular disease are up for debate, the recommendations for aspirin's use as secondary prevention are more uniform. Daily low-dose aspirin is commonly used as secondary prevention for patients with known cardiovascular disease because it is shown to reduce stroke and coronary events in this population (Calderone et al., 2021).
Although these new USPSTF recommendations provide some more guidance as to whom to consider prescribing low-dose aspirin as primary prevention for cardiovascular disease, the recommendations are broad. Advising providers to prescribe aspirin on an individual basis does not provide specific recommendations to follow to know which patients eligible to take daily low-dose aspirin would benefit the most. A major consideration the USPSTF recommendation mentions to consider before prescribing aspirin on an individual basis is age. One of the biggest risk factors for cardiovascular disease is age, with increasing age risk of cardiovascular disease and risk of bleeding increase, and starting aspirin therapy has smaller benefits as one ages (USPSTF, 2022).
Although the USPSTF recommendations are against initiating aspirin therapy as primary prevention for cardiovascular disease over the age of 60 years, if a patient is already on aspirin, the recommendation is to stop taking daily aspirin around 75 years old. Therefore, if a provider sees a patient older than 60 years who has already been taking daily low-dose aspirin for primary prevention, the patient should continue the therapy assuming the patient has not had incidences of bleeding or other complications.
Although conducting research about aspirin's use as primary prevention, many research articles mentioned other forms of effective primary prevention for cardiovascular disease aside from aspirin use. One common recommendation is the use of statins for primary prevention of cardiovascular disease. The USPSTF recommends that all adults between the ages of 40-75 years who have no history of cardiovascular disease but have a cardiovascular risk factor and a 10-year cardiovascular event risk of 10% or greater should be started on a low or moderate dose of a statin (Bibbins-Domingo et al., 2016). If a provider is considering starting a patient on aspirin as primary prevention for cardiovascular disease and the patient fits the USPSTF criteria, the provider should also consider statin therapy for the patient to further reduce the risk of the patient's cardiovascular disease regardless if aspirin therapy is initiated.
Another intervention that has significant data in its effect to reduce cardiovascular disease is lifestyle modifications. Through adhering to regular physical activity, eating nutritious meals, weight management, and smoking cessation, patients can reduce their risk of cardiovascular disease by up to 80% (Rippe, 2018). Although making these lifestyle modifications are not easy because of various barriers including finances, resources, and motivation, they could significantly reduce the risk of cardiovascular disease without risks such as bleeding. Providers should have conversations with patients about achievable lifestyle modification goals to help reduce cardiovascular risk. Even if a patient is started on aspirin therapy, lifestyle modification should still be emphasized because they are helpful tools to help reduce cardiovascular risk factors regardless.
Conclusion
As cardiovascular disease is the leading cause of death in the United States, it is imperative to find ways to prevent cardiovascular disease and death to help improve quality of life, lower health care burden, and reduce cost. Regardless of what field a provider works in, he or she will encounter patients who have or are at risk of developing cardiovascular disease. It is crucial for providers to be educated on the most up-to-date recommendations and guidelines regarding which patients should be on aspirin as primary prevention for cardiovascular disease.
The overall finding of this review is that daily low-dose aspirin does not significantly reduce a patient's risk of cardiovascular disease as primary prevention. In addition, the use of daily aspirin can increase the patient's risk of bleeding. Although the data have limitations, it seems to be leaning toward only starting patients with multiple risk factors for cardiovascular disease between the ages of 40-59 years on aspirin. However, millions of individuals take low-dose aspirin daily for primary prevention of cardiovascular disease, although there may not be enough research to support it. Clinicians must discuss with patients the benefits and downfalls, such as bleeding risk, of starting aspirin therapy as primary prevention for cardiovascular disease, as well as consider other therapies such as statins and lifestyle changes.
This review was useful in summarizing the current research on using aspirin as primary prevention for cardiovascular disease and understanding the need for further research on the topic. The review emphasizes that the current literature recommends clinicians make personalized recommendations for aspirin usage as primary prevention based on the patient's risk factors. The literature also seems to suggest that if the patient has no cardiovascular risk factors, aspirin therapy should not be started.
The question arises for future research, "Which risk factors would warrant a 40-59 year old the most benefit from daily low-dose aspirin?" An additional area of future research based on the findings by Ikeda et al. (2014) should include, "Should individuals be taking daily low-dose aspirin to reduce their risk of nonfatal myocardial infarction and transient ischemic attack if it does not reduce the risk of cardiovascular death overall?"
Acknowledgments:The author acknowledges Dr. Deborah Becker, Dr. Desiree Fleck, Dr. Patricia Pawlow, Ms. Heidi Elgart, and Ms. Patricia Griffith for their mentorship on this manuscript.
References