September 2019, Volume XXXIII, No 6

Cardiology

Aspirin for primary prevention

The message has not changed

he safety and appropriateness of taking aspirin to prevent a heart attack or stroke has been the subject of debate in recent months. Should aspirin be taken to prevent a first heart attack or stroke? How does one balance the risk reduction for myocardial infarction (MI) or stroke with the risk of bleeding on aspirin? Should aspirin instead be recommended only for secondary prevention?

Recent randomized, controlled trials, along with the 2019 Guideline on the Primary Prevention of Cardiovascular Disease issued by the ACC/AHA (American College of Cardiology/American Heart Association), have renewed our focus on aspirin’s utility for primary prevention of cardiovascular disease (CVD). Yet, despite the public and professional media coverage to the contrary, the fundamental message has not changed: Consider low-dose aspirin for primary prevention among adults for whom it is appropriate.

For patients who may be confused by news headlines regarding aspirin risk—and for the health care providers who treat them—the University of Minnesota’s “Ask About Aspirin” program, part of a multi-faceted public information campaign, provides a wealth of background information, along with an online tool to estimate 10-year and lifetime risks for atherosclerotic cardiovascular disease (ASCVD)

What does the 2019 ACC/AHA Guideline say?

The Top 10 Take-Home Messages for the Primary Prevention of Cardiovascular Disease states the following: “Aspirin should be used infrequently in the routine primary prevention of ASCVD because of lack of net benefit.” Many may interpret (and some have interpreted) this statement to suggest that aspirin is no longer effective for the primary prevention of CVD. This is not the case. Rather, the authors use this document to emphasize control of other risk factors such as hypertension and hyperlipidemia while cautioning providers on the risk of bleeding with aspirin. Later in the document, a Class IIb recommendation states that “Low-dose aspirin (75-100 mg orally daily) might be considered for the primary prevention of ASCVD among select adults 40 to 70 years of age who are at higher ASCVD risk but not at increased bleeding risk.”

The evidence still supports aspirin’s effectiveness in preventing heart attacks and strokes.

So what does this mean? It suggests that aspirin can still be effective in preventing heart attacks and strokes among adults for whom it is appropriate. The challenge lies in identification of appropriate patients. This critical decision-making is the reason health care providers are needed to comprehensively evaluate each individual for their risks and benefits, facilitating an informed decision. An algorithm accounting for CVD and bleeding risk is inadequate. The AHA/ACC statement acknowledges that patients with increased CVD risk stand more to gain from aspirin use and that there are relatively accurate tools available to assess risk. Unfortunately, bleeding risk is more difficult to quantify. Due to the complexity of the relationship between CVD risk and bleeding risk, the AHA/ACC abstains from defining a CVD risk threshold to consider aspirin, but they acknowledge that 10% is often used. Furthermore, the authors expand the age window to younger ages compared to other recommendations.

What does the 2016 U.S. Preventive Services Task Force Recommendation Statement say?

This task force recommendation is now the third national guideline (2002, 2009, 2016) that endorses the use of low-dose (81 mg) aspirin to prevent a first heart attack or stroke.

The 2016 USPSTF recommendation endorses the use of aspirin to prevent a first heart attack or stroke in men and women 50 to 59 years of age (B recommendation) and in men and women 60 to 69 years of age (C recommendation) when the 10-year cardiovascular event risk is greater than or equal to 10%. This recommendation is clear and remains accurate with the recent publications. The authors again highlight aspirin use only in those who are not at increased risk of bleeding. They also emphasize the importance of shared decision making, noting that some patients may place more value in avoiding myocardial infarction (MI) or stroke and less value in a gastrointestinal bleeding, influencing the risk/benefit threshold one might consider when initiating aspirin.

What do the aspirin randomized clinical trials show?

The 2016 USPSTF recommendation statement on primary prevention aspirin use includes 10 randomized, controlled trials to examine the effectiveness of aspirin for the primary prevention of CVD, involving over 100,000 individuals. These studies found that aspirin reduces the risk of major CVD events (total MI, total stroke, and CVD mortality) by an average of 11% (RR, 0.89, 95% CI 0.84-0.95).

Since the publication of the 2016 USPSTF recommendation on primary prevention aspirin, there have been five additional prospective randomized controlled trials, adding approximately another 50,000 subjects. These include the JPPP (2014), JPAD (2016), ASPREE (2018), ARRIVE (2018), and ASCEND (2018) studies. These studies, when added to previous studies, showed that aspirin was associated with a 15% lower risk of non-fatal MI (HR, 0.85, 95% CI 0.73-0.99), a 19% lower risk of ischemic stroke (HR, 0.81, 95% CI 0.76-0.87) at a cost of increased bleeding (Zheng SL et al., JAMA 2019;321:277-287).

It is important to point out that two of these five trials enrolled elderly people over 70 years of age (ASPREE=mean age 74 and JPPP=mean age of 71). This is a population group who are not included in the target age groups for primary prevention aspirin use in the 2016 USPSTF and 2019 ACC/AHA guidelines. The ASCEND trial only enrolled adults with diabetes mellitus and the ARRIVE trial enrolled low to moderate risk adults. The authors from the ARRIVE and ASCEND trials did note that most GI bleeding could be easily controlled while the cardiovascular endpoints resulted in significant disability or death. They did not suggest removing aspirin as primary prevention but emphasized the importance of clinician advice.

What the research shows

In secondary prevention, there is no controversy: aspirin saves lives. Yet, aspirin may also be effective if we were able to deliver it safely one minute, one day, or weeks prior to a heart attack or stroke.

However, there is not a clear distinction between primary or secondary prevention. There is merely a “continuum of risk.” If risk is high enough, aspirin can provide benefit. All individualized cardiovascular prevention requires risk assessment. We effectively and safely lower CVD risk with multi-drug antihypertensive, diabetic, and lipid-modifying treatments every day. Aspirin can be prescribed with similar safety and benefit.

The recent randomized, controlled trials, the 2019 ACC/AHA guidelines, and the 2016 USPSTF recommendations do not dispute the effectiveness of aspirin for the primary prevention of CVD events. They do, however, recognize the risk of major bleeds and recommend clinical judgment when prescribing aspirin to patients so that benefits may be increased and harm reduced.

The primary question is whether the benefit … outweighs the harm from a potential bleeding event.

How does one identify an appropriate primary prevention aspirin candidate?

While the target age groups and ASCVD risk thresholds vary across guidelines and over time, the evidence still supports aspirin’s effectiveness in preventing heart attacks and strokes. The primary question is whether the benefit of averting a potential heart attack or stroke outweighs the harm from a potential bleeding event. Recent clinical trials demonstrate that starting aspirin in elderly patients (>70 years) may be harmful but should be considered in younger adults.

Consider the following when discussing starting aspirin with your patient for primary prevention:

  • Patient is at low risk of GI bleeding (no history of GI bleeding, daily use of NSAIDs or any other anti-clotting medications).
  • Patient’s ASCVD risk is high (≥ 10% ten year ASCVD risk, according to 2016 USPSTF recommendation).
  • Patient is between 50–69 years old (2016 USPSTF recommendation).
  • Patient’s co-morbidities and family history of CVD.
  • Patient is not allergic to aspirin.
  • Patient’s preference to avert a heart attack or stroke vs. to risk a GI bleed (patient’s evaluation of benefit vs. harm)

How about my patients already using aspirin for primary prevention?

Fewer research studies have addressed this question, yet a recent study in Sweden found that aspirin discontinuation led to increased CVD events among over 600,000 adults using aspirin for primary or secondary prevention (Sundstrom J et al., Circ 2017;136(13):1183-1192). When adults using aspirin for primary prevention were examined, aspirin discontinuation led to a 28% higher rate of CVD events when compared to those with aspirin continuation. Notably, the mean age in this study was 73 years old, above the recommended age cutoff identified in recent studies. The benefit of aspirin was consistent in subgroup analysis of patients <70 and ≥70 years. This finding suggests that patients who start aspirin—and tolerate it without a major bleeding event—may benefit from continuation even into older age.

What resources are available?

The Minnesota Heart Health Program (MHHP) at the University of Minnesota received NIH funding to study the effectiveness of a statewide intervention to increase appropriate primary prevention aspirin use. Efforts are made to increase public and provider awareness of the appropriate indications for aspirin use. Community efforts included social media-based education as well as traditional media outlets. There is also a clinical intervention seeking to develop quality improvement efforts around identifying primary prevention aspirin candidates.

To support these efforts, MHHP has developed a toolkit of resources for clinics and physicians that includes a risk calculator, electronic and printed educational materials, brochures, and infographics regarding aspirin use. These materials can be found at www.askaboutaspirin.umn.edu under the partner toolkit and the calculator at www.askaboutaspirin.umn.edu/calculator. It is our goal to facilitate the use of aspirin to reduce first CVD events when appropriate and to help avoid use in those with elevated bleeding risk.

Russell V. Luepker, MD, MS, is Mayo Professor of Public Health at the University of Minnesota. Dr. Luepker’s expertise is in heart health and cardiovascular epidemiology and prevention. Much of his profession has been devoted to community-based surveillance of cardiovascular disease. He leads the Minnesota Heart Health Program and its Ask About Aspirin campaign.

Jeremy R. Van’t Hof, MD, is a Preventive Cardiologist at the University of Minnesota who has helped lead the Minnesota Heart Health Program and its Ask About Aspirin campaign for over four years. His clinical and research focus relates to increasing evidence-based medical therapy and decreasing disparities in preventive care.

Niki C. Oldenburg, DrPH, MPH, is a cardiovascular disease prevention and evaluation scientist in the Cardiovascular Division at the University of Minnesota. She strives to promote multi-disciplinary and novel approaches to the prevention of cardiovascular disease with the ultimate goal of improving our communities’ health and well-being.

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Niki C. Oldenburg, DrPH, MPH, is a cardiovascular disease prevention and evaluation scientist in the Cardiovascular Division at the University of Minnesota. She strives to promote multi-disciplinary and novel approaches to the prevention of cardiovascular disease with the ultimate goal of improving our communities’ health and well-being.