Aspirin: Should it Stay or Should it Go? Materials

ASPIRIN: SHOULD IT STAY OR SHOULD IT GO?

Pamela Sardo, PharmD, BS

Pamela Sardo, PharmD, BS, is a freelance medical writer and currently licensed pharmacist in 3 states. She is the founder and principal at Sardo Solutions in Texas. Pam received her BS from the University of Connecticut and her PharmD from the University of Rhode Island. Pam’s career spans many years in retail, clinics, hospitals, long-term care, Veterans Affairs, and managed health care responsibilities across a broad range of therapeutic classes and disease states.

Topic Overview

For decades, pharmacy teams have provided patients with acetylsalicylic acid (ASA), also known as aspirin. It is one of the most prescribed analgesic, antipyretic, and anti-inflammatory agents. It has also been used to reduce the risk of cardiovascular disease (CVD), cardiovascular mortality, and colorectal cancer. However, in recent years, scientists and clinicians have questioned whether the benefits of aspirin use outweigh the risks. The US Preventive Services Task Force (USPSTF) commissioned a systematic review on the effectiveness of aspirin in reducing the risk of CVD events (myocardial infarction and stroke), cardiovascular mortality, and all-cause mortality in persons without a history of CVD. New guidance from the USPSTF recommends against using low-dose aspirin in patients over 60 for primary prevention of atherosclerotic cardiovascular disease (ASCVD). Low-dose aspirin continues to be recommended for secondary prevention for patients with ASCVD or who have existing heart problems. Safety considerations for patients taking aspirin and patient counseling tips are also discussed.

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Universal Activity Number (UAN): The ACPE Universal Activity Number assigned to this activity is 

Pharmacist  0669-0000-24-115-H01-P

Pharmacy Technician  0669-0000-24-116-H01-T

Credits: 1 contact hour(s) (0.1 CEU(s)) of continuing education credit

Type of Activity: Knowledge

Media: Internet/Home study Fee Information: $4.99

Estimated time to complete activity: 1 contact hour(s) (0.1 CEU(s)), including Course Test and course evaluation

Release Date: August 14, 2024 Expiration Date: August 14, 2027

Target Audience: This educational activity is for pharmacists and pharmacy technicians

How to Earn Credit: From August 14, 2024, through August 14, 2027, participants must:

Read the “learning objectives” and “author and planning team disclosures;”

Study the section entitled “Educational Activity;” and

Complete the Course Test and Evaluation form. The Course Test will be graded automatically. Following successful completion of the Course Test with a score of 70% or higher, a statement of participation will be made available immediately. (No partial credit will be given.)

Credit for this course will be uploaded to CPE Monitor®.

Learning Objectives: Upon completion of this educational activity, participants should be able to:

Identify conditions where aspirin is indicated

Review the new recommendations by the US Preventive Services Task Force (USPSTF) on the use of aspirin in Cardiovascular disease (CVD) events

Describe patient counseling tips for patients taking aspirin

List safety considerations for patients taking aspirin

Disclosures

The following individuals were involved in developing this activity: Pamela Sardo, PharmD, BS. Pamela Sardo has no conflicts of interest or financial relationships regarding the subject matter. There are no financial relationships or commercial or financial support relevant to this activity to report or disclose by RxCe.com or any of the individuals involved in the development of this activity.

© RxCe.com LLC 2024: All rights reserved. No reproduction of all or part of any content herein is allowed without the prior, written permission of RxCe.com LLC.

Educational Activity

Aspirin: Should it Stay or Should it Go?

Introduction

For decades, aspirin has been prescribed as an analgesic, antipyretic, and anti-inflammatory agent. It has also been used to reduce the risk of cardiovascular disease, cardiovascular mortality, and colorectal cancer. Pharmacy team members have provided aspirin to patients for these purposes for many decades. However, in recent years, scientists and clinicians have questioned whether the benefits of aspirin use outweigh the risks. This course explores the current research on this question, and possible future therapeutic aspirin uses for patients, for example, those with liver disease.

Aspirin and Its Uses

Aspirin is one of a group of drugs called non-steroidal anti-inflammatory drugs (NSAIDs). Acetylsalicylic acid (ASA), also known as aspirin, is one of the most prescribed analgesic, antipyretic, and anti-inflammatory agents. Over 17 million prescriptions were written for aspirin in 2021 in the United States,1 and over 40% of the US population over age 40 consume aspirin regularly.2

This discussion is important because aspirin is used for cardiovascular risk reduction, including strokes and myocardial infarctions. Cardiovascular disease (CVD) is the leading cause of mortality in the US, accounting for more than 1 in 4 deaths. Each year, an estimated 605,000 people in the US have a first myocardial infarction, and an estimated 610,000 individuals experience a first stroke.3 Patients also rely on aspirin for coronary conditions, such as angina. Patients use it for fever, pain, and rheumatologic diseases, including osteoarthritis or ankylosing spondylitis.

The USPSTF’s Review of Aspirin in Cardiovascular Disease

In 2022, the US Preventive Services Task Force (USPSTF) published a review of the effectiveness of aspirin in reducing the risk of CVD events (myocardial infarction and stroke), cardiovascular mortality, and all-cause mortality in persons without a history of CVD.3 The review also investigated the effect of aspirin use on colorectal cancer (CRC) incidence and mortality in primary CVD prevention populations, as well as the harms (particularly bleeding) associated with aspirin use.3

Primary prevention of CVD refers to strategies to help prevent heart disease and stroke.3 Secondary prevention of CVD refers to strategies to reduce the risk of a recurrent cardiovascular event in patients who already have CVD.3

The updated USPSTF recommendations replace the USPSTF 2016 statements.3 The recommendations generally align with the 2019 American College of Cardiology (ACC) and American Heart Association (AHA) Guidelines on the Primary Prevention of Cardiovascular Disease.3-5 The ACC and AHA stated that aspirin should be used infrequently in the routine primary prevention of ASCVD.4,5

The USPSTF recommends against using low-dose aspirin in patients over

60 years of age for primary prevention of atherosclerotic cardiovascular disease (ASCVD).3,4 The USPSTF and the ACC recommend low-dose aspirin for secondary prevention for patients with ASCVD or those individuals who have existing heart problems.3,4 These heart problems can include a history of a heart attack, stroke, or angioplasty.4 Angioplasty is also known as percutaneous coronary intervention (PCI). PCI is a treatment that removes plaque buildup and opens blocked arteries. The heart problems may also include coronary artery bypass graft (CABG).4 The secondary prevention intervention should be based on the clinician's judgment and long-term antiplatelet strategy.4

Key Takeaway:

Updated USPSTF Recommendations on Aspirin in CVD patients:

No for Primary Prevention

Yes for Individualized Secondary Prevention

The recommendations are also stratified by age. In adults between ages 40 and 59, the recommendations discuss the use of aspirin in the primary prevention of ASCVD. The decision to initiate low-dose aspirin use for the primary prevention of CVD in adults aged 40 to 59 years who have a 10% or greater 10-year CVD risk should be an individual one.3 The individual decision is due to the USPSTF authors’ conclusion with moderate certainty that aspirin use for the primary prevention of CVD events in adults aged 40 to 59 years with a 10% or greater 10-year CVD risk has a small net benefit in relation to the risk of bleeding.3 The USPSTF concludes with moderate certainty that initiating aspirin use for the primary prevention of CVD events in adults 60 years or older has no net benefit.3 As clinicians review this information, they may note that moderate certainty is not as strong as high certainty, and small net benefit is not as strong as high net benefit.

The USPSTF review included 11 randomized trials of low-dose aspirin (100 mg daily or less) in adults aged 40 to 50 and those over 60. It also stated that “persons who are not at increased risk for bleeding and are willing to take low-dose aspirin daily” are more likely to benefit.3 The magnitude of the lifetime benefits is greater when aspirin is initiated at a younger age.3 These USPSTF recommendations on the initiation of aspirin do not apply to patients with a prior history of heart attack, stroke, bypass surgery, or recent stent procedure.4

Hypothetical Patient Case

Question:

Which scenario would aspirin treatment most likely confer CV benefit?

A 79-year-old man with hypertension and chronic kidney disease

A 53-year-old man with diabetes and 10-year ASCVD risk > 12% Answer:

A 53-year-old man with diabetes and 10-year ASCVD risk > 12%

Assessment of CVD Risk

Older age is one of the strongest risk factors for CVD.3 Men have a higher overall CVD burden, although women experience higher mortality from certain cardiovascular events, such as stroke.3 Men tend to experience CVD events earlier in life compared with women.3 The burden of CVD also differs by race and ethnicity.6 Among both sexes, Black persons have the highest prevalence of CVD.6,7

The USPSTF, National Heart, Lung, and Blood Institute (NHLBI), European and Canadian guidelines for primary prevention of CVD recommended the use of absolute risk assessment for decision-making about the intensity of lifestyle and pharmacological preventive interventions.7 To date, The ACC/AHA risk estimator is the only US-based CVD risk prediction tool that has published external validation studies in other US-based populations.7 Table 1 lists components within the risk estimator.

Table 1

The ASCVD Risk Estimator Components8

The estimator has separate equations based on sex and for Black persons and non-Black persons.7 The equations include the risk factors of age, cholesterol levels, systolic blood pressure level, antihypertension treatment, presence of diabetes, and smoking status.7 The equation also focuses on clinical outcomes of myocardial infarction and death from coronary heart disease, ischemic stroke, and stroke-related death.7 As mentioned, increasing age and ethnicity heavily influences the ACC/AHA estimated 10-year CVD event risk.7

The ACC/AHA primary prevention guidelines recommend the following:4

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

Low-dose aspirin 75-100 mg orally daily should not be administered on a routine basis for the primary prevention of ASCVD among adults

>70 years of age.

Low-dose aspirin 75-100 mg orally daily should not be administered for the primary prevention of ASCVD among adults of any age who are at increased risk of bleeding.

Point to Ponder:

When a patient comes to the pharmacy counter with an aspirin-containing over-the-counter medication, what would prompt you to ask the patient questions?

The following are key points to remember about the USPSTF report on aspirin for primary prevention:

Aspirin therapy is not a one-size-fits-all therapy. While aspirin therapy may benefit some patients, the risk-benefit ratio may not be favorable for others.

Early trials of aspirin use in primary prevention initially showed benefits, including a reduction in myocardial infarction risk in the Physicians’ Health Study.9 Subsequent studies, including the Women’s Health Study, identified a reduction in stroke risk.10

In 2018, three key trials of primary prevention with aspirin were published.

First, the ASPREE trial found that among healthy older patients (aged ≥65 years), the use of low-dose daily aspirin was associated with increased risk for mortality (5.9% vs. 5.2% for placebo at a median of 4.7 years) and cancer mortality (3.1% vs. 2.3%).11 There were similar rates of major bleeding (0.3% in both groups).11

Second, the ASCEND trial in patients with diabetes found that the use of daily low-dose aspirin reduced the risk of CVD events more than the use of placebo (8.5% vs. 9.6%, mean 7.4 years of follow-up) but was offset by increased major bleeding risk (4.1% vs. 3.2%).12

Third, the ARRIVE trial assessed middle-aged and older adults at intermediate risk for ASCVD with and without diabetes. In those without diabetes, the authors found a nonsignificant reduction in ASCVD events (4.29% vs. 4.48%, median five years of follow- up) but a doubling of gastrointestinal bleeding (0.97% vs. 0.46%).13

The TIPS-3 trial randomized patients at elevated risk for ASCVD to receive aspirin or placebo in addition to a pill containing statin and antihypertensive medications.14 A significant reduction in CVD events (4.1% vs. 5.8% over a mean of 4.6 years) resulted among patients randomized to receive aspirin.14

In 2019, the ACC and AHA guidelines recommended that aspirin could harm primary prevention in patients aged ≥70.15 They also focused on individual decision-making regarding aspirin use.

Aspirin Patient Counseling Tips

Pharmacists have a vital role in monitoring medication use. Pharmacy technicians are valuable team members and assist patients with over-the- counter medications, execute prescription processing, and much more. It is important to guide the consumers to read the product labels of aspirin products that they self-select from store shelves. It is also important to review the prescription profile for comorbid conditions. Pharmacy professionals should also review the profile to prevent duplicate therapy or drug interactions. People who are allergic to nonsteroidal anti-inflammatory agents, such as ibuprofen, should not take aspirin without speaking to a healthcare professional, as there is cross-reactivity.16 Patients who have asthma should be cautious about taking aspirin if they have asthma or known bronchospasm

associated with NSAIDs.16 Patients with an allergy to aspirin, uncontrollable blood pressure, severe liver or kidney disease, or bleeding disorders generally should not take aspirin.16 Patients should also be counseled about bleeding risks associated with chronic heavy alcohol use while taking aspirin. Advise patients that all medications should be kept out of the reach of children. Educate patients not to take more or less aspirin than prescribed or to take it more often than directed by the package label or prescription. If indicated, swallow an extended-release aspirin tablet whole with a full glass of water.17 Do not break, crush, or chew an extended-release formulation.17 Consult a healthcare provider before using aspirin in late pregnancy. Discontinue aspirin and seek immediate medical help if an allergic reaction occurs.17 Aspirin may be taken with food to decrease stomach irritation. Patients should be counseled to report red or black, tarry stools or pink or brown urine.17 Contact a physician if unusual bruising occurs or coughing up blood during aspirin use.17 These patient counseling tips may be reinforced with auxiliary label placement on prescription containers.

Safety Considerations of Aspirin

Aspirin for the primary prevention of atherosclerotic cardiovascular disease (ASCVD) is neither ‘all good’ nor ‘all bad.’18 It may benefit some patients but with a narrow therapeutic window because of the risks of major bleeding, particularly intracranial and gastrointestinal hemorrhage.18 It is

important to continue to read medical literature to learn new data as the pendulum is swinging back and forth on aspirin benefits and harms.18

Data suggest that the increased incidence of bleeding associated with aspirin use occurs relatively quickly after initiating aspirin.3 Data do not suggest that aspirin has a different bleeding risk based on age, sex, presence of diabetes, level of CVD risk, or race or ethnicity.3 Although the increase in relative risk does not appear to differ based on age, the USPSTF reported the absolute incidence of bleeding, and thus, the magnitude of bleeding harm increased with age, and more so in adults 60 years or older.3

Avoid using aspirin in children who are suffering from a viral infection. Aspirin has a role in Reye’s syndrome. It has been a cause of lethal poisoning in young children. A clinician may see Reye’s syndrome, which is characterized by vomiting and followed by encephalopathy and coagulopathy. Liver failure, with microvesicular fatty infiltration, may also occur in Reye’s syndrome. As aspirin use in children declined in the 1980s, so did the diagnosis of Reye’s syndrome, which has virtually disappeared.19

Aspirin may contribute to acid-base balance disturbances.20 Salicylates stimulate the medulla's respiratory center, and patients with salicylate poisoning experience hyperventilation.20 Respiratory paralysis and circulatory collapse secondary to vasomotor depression are possible with toxic doses of aspirin.20

High doses of aspirin can cause tinnitus. Patients who have inborn coagulopathies, such as hemophilia, should avoid all salicylates. Individuals with a tendency to bleed or bruise easily, as in the setting of dengue or yellow hemorrhagic fever, should avoid the use of aspirin.

Additional Resources

What’s Next?

Research is ongoing in other therapeutic areas for patients with unmet medical needs. In one study, patients with metabolic-associated steatotic liver disease (MASLD, formerly called NAFLD) without cirrhosis took daily low-dose aspirin in a double-blind randomized trial.21,22 These participants demonstrated reductions in liver fat content over six months compared with similar patients who took a placebo.21,22 Low-dose aspirin, 81 milligrams daily, decreased liver fat and improved hepatic inflammation and fibrosis markers.21,22 This use is off-label, and additional studies are needed.

Hypertensive disorders of pregnancy (HDP), such as preeclampsia (PE) and gestational hypertension (gHTN), occur in approximately 15% of pregnant individuals.23 These disorders disproportionately affect self-identified non- Hispanic Black individuals (with the understanding that race is a socially defined construct and the inequity is related to social determinants of health),

are increasing in frequency, and are associated with short- and long-term maternal and neonatal morbidities and mortality.23

Preeclampsia is defined as hypertension arising after 20 weeks of gestational age with proteinuria or other signs of end-organ damage.24 Preeclampsia is an important cause of maternal and perinatal morbidity and mortality, particularly with early onset.24 Aspirin at doses below 300 mg selectively and irreversibly inactivates the cyclooxygenase-1 enzyme, suppressing the production of prostaglandins and thromboxane.23 It inhibits inflammation and platelet aggregation. Such an effect has led to the hypothesis that aspirin could be useful for preventing preeclampsia. The Aspirin for Evidence-Based Preeclampsia Prevention trial recently revealed that aspirin at a daily dosage of 150 mg, initiated before 16 weeks gestation, and given at night to a high-risk population reduced the incidence of preterm preeclampsia by 62%.24 A secondary analysis of the Aspirin for Evidence- Based Preeclampsia Prevention trial data also indicated a reduction in the length of stay in the neonatal intensive care unit by 68% compared with placebo.24 This result was attributed mainly to a reduction in births before 32 weeks of gestational age from preeclampsia.24

The ASPIRIN trial is a new, large, pragmatic, comparative effectiveness trial.25 The goal is to test the hypothesis that among at-risk individuals, 162 mg/day aspirin is superior to 81 mg/day in preventing HDP.25

More research is needed to improve the accuracy of CVD risk prediction in all racial, ethnic, and socioeconomic groups. More research is also needed regarding the gastrointestinal bleeding risk associated with aspirin use in populations representative of the US primary CVD prevention population.

Researchers have published that aspirin has been associated with a reduced risk of colorectal cancer and possibly of a few other digestive tract cancers. A recent meta-analysis explained the inverse association between regular aspirin use and the risk of colorectal and other digestive tract cancers. The favorable effect of aspirin increased with longer duration of use, and, for

colorectal cancer, with increasing dose.26 Aspirin can promote cancer cell death through signaling pathways associated with, or independent of, prostaglandins.27 Prostaglandin-dependent pathways involve COX-2 and prostaglandin-independent pathways involve lymphocytes. CD80 is also involved, which has a role in immunity. A new study published that metastasis was less frequent, tumor-infiltrating lymphocyte infiltration was higher among aspirin users, and CD80 mRNA expression increased following aspirin treatment.27 More studies are needed to explore the mechanism.

Summary

The USPSTF recommendation is to not initiate aspirin for primary prevention in adults 60 years or older. When looking at the lifetime benefit of continuous aspirin use, modeling data suggested little incremental benefit in continuing aspirin use beyond 75 to 80 years. Persons who meet the eligibility criteria for aspirin use at a younger age would have higher CVD risk as they age into their 60s or 70s. This population may benefit more by continuing aspirin use than persons at lower risk.

Interprofessional healthcare team members should ask patients about over-the-counter aspirin or aspirin-containing prescriptions. Aspirin patients should be monitored and counseled to optimize outcomes and prevent adverse effects. All patients should consult their healthcare professional about whether they should begin, remain on, or safely discontinue aspirin. This decision should be made after carefully reviewing the risks and benefits.

Course Test

Aspirin has been prescribed for the following conditions except

as an analgesic.

as an antipyretic.

as an antiviral agent.

as an anti-inflammatory agent.

What conditions most accurately identify when aspirin is indicated?

Angina, fever, stomach pain

Fever, pain, osteoarthritis

Angina, fever, Crohn’s Disease

Fever, pain, canker sores

Which statement correctly recites the purpose of the 2022 review of the US Preventive Services Task Force (USPSTF) on aspirin and cardiovascular disease (CVD) events?

The USPSTF published a review of the effectiveness of acetaminophen in reducing the risk of CVD events

The USPSTF assessed aspirin in myocardial infarction and gout

The USPSTF assessed acetaminophen in stroke and cardiovascular mortality

The USPSTF published a review of the effectiveness of aspirin in reducing the risk of CVD events

Which statement below is consistent with the new recommendations by the US Preventive Services Task Force (USPSTF) on the effectiveness of aspirin?

The American College of Cardiology (ACC) and American Heart Association (AHA) stated that aspirin should be used infrequently in the routine primary prevention of ASCVD.

The ACC and AHA stated that aspirin should be used weekly in the routine primary prevention of ASCVD.

The ACC and ADA stated that aspirin should be used infrequently in the routine primary prevention of ASCVD.

The ACC and AHA stated that aspirin should be used routinely, twice daily, as a primary prevention of ASCVD.

Which persons did the USPSTF state would likely benefit from the use of aspirin?

Persons who are at increased risk for bleeding

Persons willing to take low-dose aspirin weekly

Persons who are not at increased risk for bleeding

Persons willing to take 500 mg of aspirin daily

The decision to initiate low-dose aspirin use for the primary prevention of CVD in adults aged 40 to 59 who have a 10% or greater 10-year CVD risk

should be mandatory.

should be made on a case-by-case basis.

is contraindicated in all cases.

should be considered for female patients only.

The USPSTF recommends against using low-dose aspirin

as a primary prevention for the risk of atherosclerotic cardiovascular disease (ASCVD) in patients over 30.

for secondary prevention in patients with ASCVD.

in patients who have existing heart problems.

as a primary prevention for the risk of ASCVD in patients over 60.

A pharmacist’s counseling tips to patients taking aspirin are least likely to include advice to

use aspirin with caution in patients with asthma.

use aspirin with caution in patients with bleeding risks.

consult a healthcare provider before using aspirin in late pregnancy.

consult a healthcare provider before using aspirin for a headache.

A 9-year-old asthmatic child has a 100℉ fever and is developing a cold. There are warnings about Reye’s syndrome in children associated with some NSAID medication. Which NSAID is associated with Reye’s syndrome?

Acetaminophen

Celecoxib

Aspirin

Montelukast

Which of the following is not a risk associated with aspirin use?

Impetigo

Allergy to ibuprofen

History of a bleeding ulcer

Black stools

References

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Hira RS, Gosch KL, Kazi DS, et.al. Potential Impact of the 2019 ACC/AHA Guidelines on the Primary Prevention of Cardiovascular Disease Recommendations on the Inappropriate Routine Use of Aspirin and Aspirin Use Without a Recommended Indication for Primary Prevention of Cardiovascular Disease in Cardiology Practices: Insights From the NCDR PINNACLE Registry. Circ Cardiovasc Qual Outcomes. 2022;15(3):e007979. doi: 10.1161/CIRCOUTCOMES.121.007979

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%20if%20allergic%20reaction%20occurs. Accessed July 26, 2024.

Lloyd-Jones DM. USPSTF Report on Aspirin for Primary Prevention. JAMA Cardiol. 2022;7(7):667–669. doi:10.1001/jamacardio.2022.0935

Mount M, Toltzis P. 50 Years Ago in The Journal of Pediatrics: Aspirin and Reye Syndrome. J Pediatr. 2020;222:192. doi: 10.1016/j.jpeds.2020.01.039

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Polyzos SA, Chrysavgis L, Vachliotis ID, Chartampilas E, Cholongitas E. Nonalcoholic fatty liver disease and hepatocellular carcinoma: Insights in epidemiology, pathogenesis, imaging, prevention and therapy. Semin Cancer Biol. 2023;93:20-35. doi: 10.1016/j.semcancer.2023.04.010

Effectiveness of Two Aspirin Doses for Prevention of Hypertensive Disorders of Pregnancy: ASPIRIN TRIAL (ASPIRIN) Clinicaltrials.gov. June 21,2024.

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Rolnik DL, Nicolaides KH, Poon LC. Prevention of preeclampsia with aspirin. Am J Obstet Gynecol. 2022;226(2S):S1108-S1119. doi: 10.1016/j.ajog.2020.08.045

Effectiveness of Two Aspirin Doses for Prevention of Hypertensive Disorders of Pregnancy: ASPIRIN TRIAL (ASPIRIN) Clinicaltrials.gov. June 21,2024.

https://clinicaltrials.gov/study/NCT06468202?term=Aspirin&aggFilters= status:not rec&rank=1. Accessed July 24, 2024.

Bosetti C, Santucci C, Gallus S, Martinetti M, La Vecchia C. Aspirin and the risk of colorectal and other digestive tract cancers: an updated meta-analysis through 2019. Ann Oncol. 2020;31(5):558-568. doi: 10.1016/j.annonc.2020.02.012

Simoni O, Scarpa M, Castagliuolo I. et. Al. IMMUNOREACT 7: Regular aspirin use is associated with immune surveillance activation in colorectal cancer. Cancer. 2024;130(13):2272-2286. doi:10.1002/cncr.35297

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