Issue: April 2019
April 08, 2019
11 min read

Aspirin therapy for primary prevention of CVD requires individualized approach

Issue: April 2019
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The use of aspirin for the primary prevention of CVD continues to perplex the cardiology community, especially after the publication of three randomized controlled trials of aspirin in 2018 and a new guideline suggesting the practice should not be done in most patients.

Three large trials of aspirin — ASCEND, ARRIVE and ASPREE — generated much conversation. In these large trials of patients at varying degrees of risk who had never had a CVD event, the magnitude of ischemic benefit of aspirin was significant in ASCEND but smaller and not statistically clear in the other two studies; however, the risk for major bleeding associated with aspirin was consistently elevated compared with placebo in all three studies. Reaction to the trials varied widely, with some cardiologists concluding aspirin has no benefit in primary prevention and others concluding that it still has benefit in certain circumstances.

At the American College of Cardiology Scientific Session in March, the ACC and American Heart Association unveiled a new prevention guideline that advises against the routine use of aspirin for primary prevention unless CVD risk is very high; this was based on the three 2018 trials and a meta-analysis of those and some earlier trials published in JAMA in January, which concluded that aspirin reduced major CV events but increased bleeding in the primary prevention population.

The guideline advised that aspirin should not be used for primary prevention in patients aged 70 years or older and in patients at high bleeding risk. The authors wrote that aspirin may be considered for primary prevention in patients aged 40 to 70 years at high risk for atherosclerotic CVD and low risk for bleeding (Commentary).

Jeffrey S. Berger, MD, from NYU Langone Health, said a patient should only use aspirin for primary prevention if the ischemic benefit outweighs the bleeding risk.
Source: NYU Langone Health. Printed with permission.

Cardiologists play an important role to guide patients if they require or are even considering aspirin therapy, which involves CVD risk and bleeding risk assessments.

“What is critically important is the benefit-risk assessment for the individual patient,” JoAnn E. Manson, MD, DrPH, FAHA, chief of the division of preventive medicine at Brigham and Women’s Hospital and professor of medicine and the Michael and Lee Bell Professor of Women’s Health at Harvard Medical School, told Cardiology Today. “It will vary substantially from patient to patient in terms of what their underlying CVD risk is, what their bleeding risk factors are and also their personal preferences regarding use of aspirin.”


Recent data on aspirin

The recent ASCEND, ARRIVE and ASPREE trials were undertaken because, while the benefits of aspirin were proven to outweigh risks in secondary prevention, and its risks do not clearly outweigh its benefits in primary prevention in low-risk populations, little was known about the risk-benefit balance in intermediate-risk populations, ASCEND investigator Jane Armitage, FRCP, FFPH, professor of clinical trials and epidemiology and honorary consultant in public health medicine at the University of Oxford, said in an interview.

“These three trials were hoping to target intermediate risk,” she said. “In the ASCEND trial, we were interested in the diabetic population, knowing that those people are at higher risk than healthy individuals of the same age and gender, but much lower risk than people who’ve had an MI or a stroke. Similarly, ARRIVE had aimed to enroll people based on their calculated risk, but all three of the trials showed much lower than expected rates of vascular disease events.”

In the ASPREE trial, patients older than 70 years assigned low-dose aspirin had an increased risk for major hemorrhage with no significant decreases in the risk for CVD after a median follow-up of 4.7 years (Table).

“For ASPREE, it depends on how strictly the results are interpreted,” ASPREE investigator John J. McNeil, MBBS, PhD, FRACP, head of the department of epidemiology and preventive medicine and of the school of public health and preventive medicine at Monash University in Australia, told Cardiology Today. “Strictly speaking, ASPREE told us that commencing low-dose aspirin therapy in a person aged 70 years or above for primary prevention does not lead to any net benefit.”

John J. McNeil

Patients assigned aspirin in the ARRIVE trial had similar rates of serious adverse events, treatment-related adverse events and the primary endpoint, defined as a composite outcome of time to first occurrence of MI, CV death, stroke, unstable angina or transient ischemic attack, compared with those assigned placebo after a median follow-up of 60 months. Gastrointestinal bleeding events were higher in the aspirin group vs. the placebo group (Table).

In contrast, patients from the ASCEND trial assigned aspirin had lower rates of serious vascular events compared with those assigned placebo during a mean follow-up of 7.4 years. Major bleeding was higher in the aspirin group compared with the placebo group (Table).

Identifying appropriate patients

Identifying patients who are appropriate for aspirin therapy for primary prevention of CVD is critical in shared decision-making, although it is difficult without knowledge of who clearly benefits from the therapy.


“I do not think at the moment there is any good evidence for treating people in general in primary prevention, but the question then arises: Can you find a population who would particularly benefit?” Armitage said. “When we looked even among the 20% who were at highest risk, the vascular events avoided by aspirin do slightly outweigh the number of major bleeds that’s caused, but it is still fairly finely balanced.”

There may be some hints as to who may benefit from aspirin therapy.

“[Aspirin therapy may be suitable for] somebody who looks like they have a very high risk of coronary disease either because they have a fairly positive CT calcium score, have a very nasty family history or have very high lipids and who are not tolerating, for example, statins,” Joseph S. Alpert, MD, professor of clinical translational sciences and of medicine at the Sarver Heart Center at the University of Arizona in Tucson and Cardiology Today Editorial Board Member, said in an interview. “There was a while where we said everyone over 50 [years] should be taking aspirin. We are backing away from that.”

Joseph S. Alpert

Whether a patient will benefit from aspirin therapy or have a bleeding event varies from patient to patient, making it somewhat difficult to identify specific patient populations.

“I wish I could [say that in] these patients, the benefit outweighs the risk and it was very clear cut, but it is not,” Jeffrey S. Berger, MD, associate professor of medicine and surgery and co-director at the Center for the Prevention of Cardiovascular Disease at NYU Langone Health, said in an interview. “It is quite simplistic to think that based on an individual’s age, blood pressure or cholesterol, someone should be on a drug that inhibits platelet function.”

Some would assume that older patients may benefit from aspirin therapy for the primary prevention of CVD, but as shown in the ASPREE trial, it did not prolong disability-free survival or improve general health in these patients.

“Ultimately that is what an elderly person taking a preventive medication would be looking for,” McNeil said.

Continuum of risk

Event rates for patients in the ARRIVE, ASPREE and ASCEND trials were lower than expected, specifically for CVD, serious vascular events and a composite of time to first occurrence of MI, CV death, stroke, unstable angina or TIA. These lower event rates may have been a result of lifestyle changes, statin use and other effective tools for primary prevention.


“The bottom line of this is, yes, we had less heart disease than predicted [in ASPREE],” McNeil said. “How much of it was due to lifestyle changes and/or statin use, I’m not 100% sure. We didn’t find any difference between the percentage reduction [of serious vascular events] in people taking statins compared with people who weren’t taking statins.”

Lifestyle changes should be emphasized as a first-line approach for the primary prevention of CVD before considering aspirin therapy.

“Many times, patients come to a health care practitioner asking for a miracle drug,” Berger said. “I tell them they have incredible power and ability to prevent heart attack or stroke by themselves via exercise, health nutritional behavior, healthy eating, stress reduction. Aspirin does have a role, but it is not the first, second or third thing that I would be talking about with my patient.”

Despite the findings in primary prevention, experts generally recommend aspirin should still be used in secondary prevention.

“It does not magically turn from aspirin being desirable in secondary prevention to no utility at all in primary prevention, regardless of baseline CVD risk,” Manson said in an interview. “It is a continuum of risk, and some patients in a primary prevention setting will have a high-enough personal risk of cardiovascular disease and a low-enough bleeding risk that they will be an appropriate candidate for aspirin. But the bar is set higher now for use in primary prevention.”

JoAnn E. Manson

Cardiologists have an added challenge when trying to guide their patients as to whether they should take low-dose aspirin. Since aspirin is available over the counter, it is easy for patients to go against their cardiologist’s guidance.

“It needs to be better publicized among healthy older people that aspirin is not actually a safe drug to be taking,” Armitage told Cardiology Today.

Sometimes it is difficult for patients to avoid aspirin when taking an over-the-counter pain medication because it is a common ingredient.

Patients who are using aspirin short term do not need to contact their cardiologist, but long-term use of the therapy should be supervised by a cardiologist or another health care provider, experts said.

“They should not be starting it for the purpose of the prevention of cardiovascular disease or other preventive or long-term purposes without discussing this with their doctor and getting their health care provider’s recommendation,” Manson said.

Unanswered questions

Questions remain regarding low-dose aspirin despite the results of the recent primary prevention trials.


One area surrounds how to identify patients who would benefit more from low-dose aspirin for primary prevention.

“We need to think about aspirin the way we think about other drugs,” Berger said. “We think about how it works, and then we figure out who is at risk because of that. If we can figure out who is at risk because of their platelets, that would be a very important way to figure out who should be on aspirin.”

Researchers from the ASCEND trial will be performing meta-analyses of individual patient data to see which patients clearly benefit or are clearly harmed from aspirin therapy.

“To be honest, I think it is very unlikely to change that underlying message,” Armitage told Cardiology Today.

The duration and exact dose of aspirin therapy should also be a focus of further research, in addition to how to reduce the risk for bleeding.

“Fortunately, there’s now a clear answer for adults aged 70 years and older, but it is still unclear how long patients should continue to take aspirin,” Manson said. “We are not talking about initiating aspirin after age 70 in the primary prevention setting, where the risks would likely outweigh the benefits. What if you start aspirin in your 50s, you have a 10-year CVD risk of 15% or greater, you start taking aspirin, you have been doing well on it and you get to age 70? Should you continue?”


More research is needed on low-dose aspirin and the incidence of cancer with long-term follow-up. Although the ASCEND trial did not find a significant difference in cancer incidence in patients taking low-dose aspirin compared with placebo, the ASPREE trial found that the aspirin group had increased risk for cancer-related death compared with the placebo group (3.1% vs. 2.3%; HR = 1.31; 95% CI, 1.1-1.56).

The recent data on aspirin use for primary prevention may provide an opportunity to update The U.S. Preventive Services Task Force guideline on aspirin use for primary prevention of CVD and colorectal cancer, which was last published in the Annals of Internal Medicine in 2016. The current guideline states that there is insufficient evidence regarding aspirin for primary prevention in patients aged 70 years and older, which should now be updated to a D recommendation, which is against the initiation of aspirin, Manson said.

While further research is needed, Alpert said there should be a shift away from the randomized, double-blind trials to focus on databases and the collection of DNA.

He added, “I would like to see some studies of the genome for it to suggest which patients are more likely to bleed with aspirin than others. I would not do another big population study. [The trials on this topic] are all well done, in large numbers and very expensive. We need to move on.”

Shared decision-making

Before a patient considers aspirin therapy, he or she should discuss the options, benefits and potential risks with a cardiologist or primary care physician. Several risk factors should be considered during this discussion, such as the ASCVD risk score, family history of premature CVD and possibly a coronary artery calcium score.

“Cardiologists will often have more information about their patient and their patient’s risk,” Armitage told Cardiology Today. “They may feel, in light of that information, that their patient is particularly at risk and they’re prepared to take the risk that they will also cause bleeding in order to protect their patients.”

Even with the available data from numerous trials, cardiologists should be aware that the trials take into consideration patients in general rather than the individual patient they are treating, experts said, noting cardiologists and other clinicians should approach this subject based on a patient’s risk for heart disease, stroke and bleeding.

“You want to make sure that their absolute benefit outweighs their absolute risk,” Berger said in an interview. “One can never be certain, but if you can do it to a certain degree, then it becomes worthwhile. Clearly there are patients that should be on aspirin for the prevention of a first heart attack or stroke. It is just a small proportion of all the patients that I see.”


Cardiologists have not been given much guidance on how to assess bleeding, but risk factors specific to bleeding with aspirin should be assessed, including comorbidities, peptic ulcer complicated by bleeding, recent ulcers, recent gastrointestinal bleeding, kidney disease and whether a patient is taking other NSAIDs, experts said.

Aspirin therapy for primary prevention should be considered once other options have been implemented including adequate cholesterol lowering, BP reduction and smoking cessation, experts said. If a patient is still at high risk after implementing other therapies, low-dose aspirin may be considered, Alpert said. He added that if a patient bleeds into the skin after initiating aspirin therapy, it can be reduced to 3 days per week.

“It requires shared decision-making with the patient,” Manson said. “Patients need to be actively engaged in these discussions. Many patients will be happy to have fewer medications and will want to avoid taking aspirin. Some patients who have been taking aspirin long term and tolerating it well, especially those with a strong family history of colorectal cancer, may want to continue taking it despite uncertainty about its balance of benefits and risks.” – by Darlene Dobkowski

Disclosures: The ARRIVE trial was funded by Bayer. The ASCEND trial was supported in part by Abbott, Bayer, Mylan and Solvay. The ASPREE trial 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. Alpert, Armitage, Berger and McNeil report no relevant financial disclosures. Manson reports she was on the data safety monitoring board for the ASPREE trial.