Aspirin Therapy for Primary Prevention of Cardiovascular Disease

Continuing Education Information:

Target Audience:

Pharmacists

Activity Type: Knowledge-Based

Learning Objectives:

1.Describe the current recommendations regarding the use of aspirin for primary prevention of cardiovascular disease.  2.Analyze the findings of recent clinical trials that studied the use of aspirin for primary prevention of cardiovascular disease.  3.Discuss patient specific recommendations regarding the use of aspirin for primary prevention of cardiovascular disease.  

Aspirin Therapy for Primary Prevention of Cardiovascular Disease

Elizabeth K. Pogge, Pharm.D., MPH, BCPS-AQ Cardiology, BCGP, FASCP, FAzPA, Professor Desiree Smith, PharmD Candidate 2022, Midwestern University College of Pharmacy - Glendale Campus Andy Lo, PharmD Candidate 2022, Midwestern University College of Pharmacy - Glendale Campus Adrian Salazar, PharmD Candidate 2022, Midwestern University College of Pharmacy - Glendale Campus Tony Huang, PharmD Candidate 2022, Midwestern University College of Pharmacy - Glendale Campus

Acknowledgement None

Funding This research was not funded.

Cardiovascular disease is the leading cause of death in the United States. Two common causes of cardiovascular death are strokes and ischemic heart disease. As such, the prevention of these events from occurring has received a lot of focus. This brings attention to one of the oldest drugs in the pharmacy arsenal, aspirin. This pharmacologic agent works by inhibiting platelet activation and decreasing the risk of clot formation, while at the same time increasing the risk of bleeding. Summary of articles: Routine use of aspirin for the primary prevention of cardiovascular disease has been debated after three large randomized, controlled trials were published. These trials concluded that aspirin for the primary prevention of cardiovascular disease in patients with a low to moderate ASCVD risk score provided minimal efficacy while increasing the risk of bleeding. The results of these trials were quick to be implementing into several guidelines that recommended against the routine use of aspirin for primary prevention of cardiovascular disease especially in patients at an increased risk of bleeding or > 70 years of age. This new data prompts shared decision making to occur between the patient and the provider when considering aspirin for the primary prevention of cardiovascular disease. Summary: Pharmacists can be an integral part of the interprofessional team by providing patient education and counseling related to aspirin use. Furthermore, pharmacists can educate providers and the public about the evolving role of aspirin for primary prevention of cardiovascular disease. Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of morbidity and mortality globally.1 According to the American Heart Association (AHA), the two most common cardiovascular-related deaths are ischemic heart disease (IHD) and stroke, followed by high blood pressure and heart failure.2 Modifiable risk factors leading up to these events are smoking, physical inactivity, nutrition, overweight/ obesity, elevated cholesterol, diabetes mellitus, and high blood pressure.1 As such, the 2019 American College of Cardiology (ACC)/AHA guidelines strongly recommend (Class I) primary prevention interventions through lifestyle modifications such as exercise, healthy diet, and smoking cessation.1 In addition to lifestyle changes, pharmacotherapy to reduce other modifiable risk factors such as blood pressure and cholesterol is strongly recommended for those at high risk.1 For the first time in decades, these guidelines recommend aspirin should be used infrequently in the routine primary prevention of ASCVD. Acetylsalicylic acid or aspirin was produced in 1897 by German Chemist Felix Hoffman as an analgesic extracted from the willow bark tree.3 Aspirin is commonly used for fever, inflammation, and pain at higher doses; however, its use is limited due to gastric side effects.4 Aspirin works by irreversibly inhibiting two isoforms of the COX enzyme. COX-1 is responsible for TXA2 production causing platelet aggregation in the arterioles. COX-2 promotes vasodilation through the up-regulation of prostaglandins. By inhibiting TXA2, aspirin inhibits platelet activation that decreases the risk of clot formation, however, increases the risk of bleeding. Aspirin use for primary prevention of cardiovascular disease is common practice among adults. The 2017 National Health Interview Survey (NHIS) found that 29 million (23.4%) United States (US) adults without cardiovascular disease over the age of 40 reported taking daily aspirin and 6.6 million (22.8%) started aspirin without a physician recommendation.5 When looking at older adults specifically, this survey found that 46.2% of adults without cardiovascular disease 70 years or older reported using aspirin.5 While aspirin use for secondary prevention of ASCVD is consistently recommended, data on primary prevention continues to evolve.6 The 2019 ACC/ AHA primary prevention guidelines mentioned above provide several new recommendations regarding aspirin for primary prevention.1 These guidelines suggest that low-dose aspirin might be reasonable (Class IIb, LOE: A) in adults 40 – 70 years of age with a higher ASCVD risk who are not at an increased risk of bleeding. Furthermore, they recommend against (Class III: harm) the routine use of low-dose aspirin for primary prevention among adults > 70 years of age or any adult who is at an increased risk of bleeding. Furthermore, the US Prevention Services Task Force is in the process of updating their recommendation regarding aspirin for primary prevention.7-8 The current draft states that adults who are 60 years or older should not be initiated on low-dose aspirin for primary prevention and adults 40 to 59 years with a 10% or greater 10-year ASCVD risk may be considered for low-dose continued on next page 23

aspirin on an individualized basis.7 This represents a shift in thinking surrounding the use of aspirin for primary prevention of ASCVD, with recent evidence pointing to a lack of benefit with routine use. The purpose of this article is to review several recently published trials that have laid the foundation for this change in aspirin recommendation and provide suggestions to pharmacists regarding counseling related to aspirin use for primary prevention. Three large randomized, controlled trials, ARRIVE, ASCEND, and ASPREE trial are responsible for many of the changes we are seeing in the guidelines regarding aspirin for primary prevention.9-12 A summary of these three trials can be found in Table 1. All three of these trials are a strong study design, randomized, double-blind, placebo-controlled,

Table 1 – Comparison of Aspirin Primary Prevention Trials

Trial ASPREE9-10 ARRIVE11 ASCEND12

Design

Study Drug Sample Size

Baseline Characteristics

Primary Outcome Randomized, double-blind, placebo-controlled, multinational

Aspirin enteric-coated 100mg daily versus placebo

19,114 Male: 44% Median age: 74 years White race: 95% Current smoker: 4% HTN:** 74% Statin use: 34% Type 2 diabetes: 11% Male: 71% Mean age: 64 years White race: 98% Current smoker: 29% HTN:** 65% Statin use: Not reported Type 2 diabetes: 0% Male: 63% Mean age: 63 years White race: 97% Current smoker: 8% HTN:** 62% Statin use: 75% Type 2 diabetes: 94%

Primary endpoint: Death from any cause, dementia, and persistent physical disabilities9 Secondary endpoint: Cardiovascular disease (defined as fatal coronary heart disease, nonfatal MI, fatal or nonfatal stroke, or hospitalization for heart failure) Safety endpoint: Major hemorrhage 12,546

Primary endpoint: Composite of time to first occurrence of cardiovascular death, MI, unstable angina, stroke, or TIA Safety endpoint: Hemorrhagic events 15,480

Primary endpoint: Time to first serious vascular event (composite including non-fatal MI, non-fatal stroke, TIA, or death from any vascular cause) Safety endpoint: First occurrence of any major bleeding event

Protocol

Results

Median follow-up 4.7 years Primary endpoint: HR 1.01 (0.92 - 1.11)9 Secondary endpoint: HR 0.95 (95% CI 0.83-1.08)10 Safety endpoint: HR 1.38 (95% CI 1.18-1.62)* Intention-to-treat

Median follow-up 5 years Primary endpoint: HR 0.96 (95% CI 0.81-1.13) Safety endpoint: Gastrointestinal bleeding HR 2.11 (95% CI 1.36-3.28)*

Median follow-up 7.4 years Primary endpoint: RR 0.88 (95% CI 0.79-0.97)* Safety endpoint: RR 1.29 (95% CI 1.09-1.52)*

Abbreviations: ASCEND = A Study of Cardiovascular Events in Diabetes ASPREE = Aspirin in Reducing Events in Elderly, ARRIVE = Aspirin to Reduce Risk of Initial Vascular Event, ASCVD = atherosclerotic cardiovascular disease, CI = confidence interval, CVD=cardiovascular disease, HTN= hypertension, HR = hazard ratio, MI= myocardial infarction, RR = rate ratio, TIA = transient ischemic attack * Statistical significance **Hypertension was defined differently between the three trials. ASPREE included those taking an anti-hypertensive agent or blood pressure >140/90 mmHg, ARRIVE included those taking an anti-hypertensive, and ASCEND included those with self-reported hypertension.

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multinational trials, looking at aspirin enteric-coated 100mg daily versus placebo. Each trial included a low number of participants in the US, which could limit the applicability of these studies to US patients. Each trial was conducted to evaluate the benefits and risks of aspirin in primary prevention so patients with baseline cardiovascular disease were excluded. Baseline characteristics between the two groups were similar in each study. Each study did an intention-to-treat analysis, with the ARRIVE trial also including a per-protocol analysis.11 The statistics in this paper will include just the intention-to-treat analysis as this data is generally considered more applicable to real life clinical practice. Each study is summarized below with important take home points. The ASPREE trial included adults ≥ 70 years old and White or ≥ 65 years old if Black or Hispanic.10 Participants were excluded if they had dementia, a disability, or were at a high risk for bleeding. For Black and Hispanic individuals, they used a lower age due to the higher risk of cardiovascular disease seen in these ethnicities. At baseline, 30% of participants were obese (body-mass index (BMI) > 30 kg/m2), 70% had 2 or more cardiovascular risk factors, and 11% had previously used regular aspirin. This trial was multicenter and included 34 sites in the US and 16 in Australia, most participants being Australian (87%). It is important to note that the primary outcome of this study was the composite of death, dementia, or persistent physical disability, while the secondary outcomes were cardiovascular and bleeding. The primary outcome was not statistically significant, with a limitation related to this outcome being the follow-up of only approximately five years. This paper focuses on the secondary outcomes, with there being no significant benefit for the use of aspirin for primary prevention of cardiovascular disease (defined as fatal coronary heart disease, nonfatal myocardial infarction (MI), fatal or nonfatal stroke, or death or hospitalization for heart failure), with a statistically significant 38% increased risk of major hemorrhage (defined as hemorrhagic stroke, symptomatic intracranial bleeding, or clinically significant extracranial bleeding). These results were consistent when looking at each endpoint of the cardiovascular outcome, with no benefit for the use of aspirin seen in any subgroup. In terms of major hemorrhaging, any intracranial bleeding and upper gastrointestinal bleeding were both increased with the use of aspirin, while fatal bleeding was not statistically significantly different between the two groups. Several limitations to this trial were noted by the authors. The trial had a low adherence rate, with only two-thirds of the participants still taking the assigned intervention at the end of the trial, which could have led to an underestimation of any benefit seen with aspirin. Furthermore, since only a small number of participants were taking aspirin prior to the trial, the results cannot give guidance on continuing or discontinuing healthy elderly individuals who have been taking aspirin for primary prevention. The ARRIVE trial studied men ≥ 55 years with two to four risk factors for cardiovascular disease and women ≥ 60 years with 3 or more risk factors.11 At baseline, the mean estimated ACC/ AHA 10-year ASCVD risk score was moderate for these participants at 17.3%. The median BMI of participants was 28 kg/m2, with 58% of participants having high total cholesterol (defined as ≥ 200 mg/ dL). Patients were excluded if they were at high risk of bleeding or had comorbid diabetes. This study was multicenter, with 90% of patients from Germany, Poland, and the United Kingdom, and only 4% from the US. The primary composite outcome of the first occurrence of MI, cardiovascular death, unstable angina, stroke, or transient ischemic attack (TIA) was not statistically significant between the aspirin and placebo group at a median follow-up of five years. These results were consistent when looking at each endpoint of the cardiovascular outcome, with no benefit for the use of aspirin seen in any subgroup. In the safety analysis, gastrointestinal bleeding was significantly higher in the aspirin group (0.97% vs 0.46%; p = 0.0007) with total serious adverse events not differing between the two groups. One limitation to this study was the low overall incidence of gastrointestinal bleeding as well as cardiovascular events. These lower event rates show some of the challenges with doing primary prevention studies, including differences in other primary prevention measures among providers, low compliance among participants, as well as difficulty in capturing events in a primary care clinic which could underestimate the actual event rate. The ASCEND trial included 15,480 participants, ≥ 40-year-old, from the United Kingdom with diabetes and without baseline cardiovascular disease.12 They excluded patients with a contraindication to aspirin. At baseline, 47% of participants were obese (BMI > 30 kg/m2), 35% were using regular aspirin before screening, and the median duration of diabetes among participants was seven years. The primary efficacy endpoint was the time to first serious vascular event, a composite of non-fatal MI, non-fatal stroke, TIA, or death. The primary safety endpoint was the first occurrence of any major bleeding event, defined as intracranial hemorrhage, sight-threating bleeding in the eye, gastrointestinal bleeding, or any other serious bleeding that resulted in hospitalization, transfusion, or death. Over a mean follow-up of 7.4 years, there was a 12% lower risk of serious vascular event in continued on next page 25

the aspirin group compared to placebo, but also a statistically significant 29% increased risk of major bleeding. The majority of first major bleeding events included gastrointestinal bleeding followed by sight threatening bleeding events in the eye and intracranial bleeding events. ASCEND was unique in the fact that recruitment, treatments, and follow ups were all done by mail, which allowed this trial to have almost complete follow-up with all patients randomized. Limitations included low adherence to aspirin in the treatment group (70%) which decreased over time while the placebo group had an increase in use of aspirin during the study which could have led to an underestimation of aspirin effectiveness.

Clinical Implications

The risk and benefits of taking aspirin for primary prevention is a duality that needs to be assessed on an individualized basis. When summarizing these three recent trials, aspirin provided a benefit in decreasing serious vascular events (vascular death, non-fatal MI, non-fatal strokes, and TIA) in diabetic men and women at least 40 years of age but did so at the expensive of increased bleeding risk.12 For adults > 70 years of age or those at moderate cardiovascular risk without diabetes, aspirin was not able to reduce cardiovascular events and consistently showed higher rates of bleeding.10 It is important to note that during all three of these trials, the cardiovascular endpoint occurred less commonly than was expected. One theory as to why this occurred is related to the increased use of other effective primary prevention strategies, most notability statins, antihypertensives, and anti-diabetic agents. With more effective primary prevention strategies, we could continue to see less benefit from aspirin therapy. The main adverse effect of aspirin that should be considered when prescribing is bleeding, which is variable based on patient demographics. Specifically, patients with diabetes mellitus and/or moderate cardiovascular risk were at an increased risk of gastrointestinal bleeding, and major bleeding with aspirin therapy.12 In addition, aspirin has shown to have an increased risk of a major hemorrhagic events in the elderly (70-years of age or older).10 In all three trials safety endpoints, gastrointestinal bleeding was statistically significantly higher in the aspirin group, reinforces the fact that gastrointestinal bleeding is a concern with aspirin therapy.10-12 When considering aspirin for primary prevention of ASCVD, a one-size-fits-all strategy is clearly not optimal. The risk of bleeding needs to be weighed against the benefit aspirin can provide. Pharmacists can play a role in screening patients for appropriate aspirin use and making patient specific recommendations regarding aspirin therapy. Additionally, pharmacist can counsel patients taking aspirin on strategies to mitigate bleeding risk, such as reducing concomitant medications that increase bleeding risk. It is important to remember that patients may not report over-the-counter medications, such as aspirin, as well as supplements or non—

Table 2 – Counseling considerations for aspirin, immediate release (tablet enteric-coated) as ASCVD primary prevention14

Dosing: Adult Immediate release: Oral: 75 to 100 mg once daily

Adverse Reactions • Gastrointestinal ulcer • Hemorrhage/bleeding (especially gastrointestinal) • Hypersensitivity reaction (immediate and delayed)

Counseling points to patients

Administration • Take with full glass of water same time each day. • If stomach upset occurs, take with food or milk.

Adverse Reactions • Report immediately signs of rashes or hives • Watch for signs of bleeding like vomiting/coughing up blood o Black, red, coffee ground appearance, or tarry stools o Bleeding from the gums o Bleeding from outer wounds that will not stop

Storage Store at room temperature in a dry place. Do not store in the bathroom. Keep out of reach from children or pets.

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steroidal anti-inflammatory drugs to their providers due to perceptions that these products are benign and safe. Therefore, pharmacists working as part of the interprofessional team can be an important tool in providing aspirin counseling to patients. A current systematic review of the US prevention service task force found that older age, male sex, and diabetes mellitus all increase the risk of serious bleeding in patients.13 Several reversible risk factors were also identified, including smoking, elevated blood pressure, and concomitant medications with antiplatelet effects. Pharmacists can assist in providing a thorough review of patient specific risk factors of aspirin associated bleeding and provide counseling related to risk factor modification.

Conclusion

Historically, aspirin has been used for many decades for a variety of therapeutic uses. While historical data showed aspirin was beneficial for the primary prevention of cardiovascular disease, newer studies have consistently shown no benefit for most adults. The increased risk of bleeding, however, remains consistent and bleeding risk should be weighed against the potential benefits of aspirin therapy in all patients. Emphasizing nonpharmacologic primary prevention strategies is important in all patients, as they have no known adverse effects, and may provide significant benefits. Still, aspirin plays a role and may be considered in some high-risk individuals. Pharmacists play an integral role in screening patients for aspirin therapy and deprescribing aspirin therapies for patients who are low to moderate ASCVD risk or at a high risk of bleeding. As new data emerges, pharmacists can continue to educate patients and providers on the benefits and risk of aspirin therapy. 

REFERENCES

1. Arnett D, Blumenthal RS, Albert MA, et al. American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2019 ACC/AHA Guideline on the

Primary Prevention of Cardiovascular Disease: A Report of the American College of Cardiology/American Heart association Task Force on Clinical Practice Guidelines. J Am

Coll Cardiol. 2019 Sep, 74 (10) e177–e232 2. Benjamin EJ, Muntner P, Alonso A, et al. Heart Disease and Stroke Statistics – 2019 Update: A report from the

American Heart Association. Circulation. 2020 Jan, 14; 141(2). 3. Singal AK, Karthikeyan G. Aspirin for primary prevention:

Is this the end of the road? Indian Heart J. 2019 Mar-

Apr;71(2):113-117. 4. Raber I, McCarthy C, Vaduganathan M, et al. The rise and fall of aspirin in the primary prevention of cardiovascular disease. Lancet 2019; 393: 2155-67. 5. O'Brien CW, Juraschek SP, Wee CC. Prevalence of Aspirin Use for Primary Prevention of Cardiovascular Disease in the United States: Results From the 2017 National Health

Interview Survey. Ann Intern Med. 2019;171(8):596-598. 6. Antithrombotic Trialists’ (ATT) Collaboration, Baigent C,

Blackwell L, et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomized trials.

Lancet. 2009;373:1849–60. 7. US Preventive Services Task Force. Aspirin use to Prevent

Cardiovascular Disease: Preventive Medication. https:// uspreventiveservicestasksforce.org/uspstf/draftrecommendation/aspirin-use-prevent-cardiovasculardisease-preventive-medication. Accessed October 16, 2021. 8. Guirguis-Blake JM, Evans CV, Senger CA, et al. Aspirin for the primary prevention of cardiovascular events: a systematic evidence review for the US Preventive Services

Task Force. Ann Intern Med. 2016; 164:804–13. 9. McNeil J.J., Woods RL, Nelson MR, et al. Effect of aspirin on disability-free survival in the healthy elderly. N Engl J Med. 379(16): 1499-1508. 10. McNeil, J. J., Wolfe, R., Woods, et al. (2018). Effect of aspirin on cardiovascular events and bleeding in the healthy elderly. N. Engl. J. Med. 379 (16), 1509–1518. 11. Gaziano, J. M., Brotons, C., Coppolecchia, et al. (2018).

Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE): a randomised, double-blind, placebo-controlled trial. Lancet 392 (10152), 1036–1046. 12. Bowman, L., Mafham, M., Wallendszus, et al. (2018). Effects of aspirin for primary prevention in persons with diabetes mellitus. N. Engl. J. Med. 379 (16), 1529–1539. 13. Whitlock EP, Burda BU, Williams SB. Bleeding risk with aspirin use for primary prevention in adults: A systematic evidence review for the US prevention services task force.

Ann Intern Med. 2016;164(12):826-835. 14. Lexicomp Online, Lexi-Drug. Aspirin. Available at: www. online.lexi.com. Accessed February 8, 2022.

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CE Questions

1. Which of the following is a strong (class I) recommendation by the 2019 ACC/AHA guidelines for primary prevention of atherosclerotic cardiovascular disease (ASCVD)? a. The intake of trans fat should be increased to reduce ASCVD risk  b. Adults should engage in 300 minutes of vigorous aerobic activity per week c. All adults should take 1 gram of over-the-counter omega-3 fatty acid  d. Tobacco abstinence is recommended for all adults to reduce ASCVD risk

2. Which of the following is a risk factor for the development of atherosclerotic cardiovascular disease? a. Obesity  b. Hyperlipidemia  c. Hypertension   d. All the above  

3. What is the mechanism of action of Aspirin? a. Irreversible inhibitor PGY12 receptor  b. Reversible inhibitor of Factor Xa  c. Irreversibly inhibits COX-1 and COX-2 enzymes  d. Irreversibly inhibits COX–2 enzymes

4. Which of the following is a correct recommendation regarding aspirin for the primary prevention of ASCVD according to the 2019 ACC/AHA guidelines?  a. Low-dose aspirin might be reasonable in adults 40 – 70 years of age with a higher ASCVD risk who are not at an increased risk of bleeding  b. Low-dose aspirin should be routinely recommended for the primary prevention of

ASCVD in all adults > 70 years of age who are not at an increased risk of bleeding  c. Low-dose aspirin should be routinely recommended for the primary prevention of

ASCVD to adults 40 – 70 years of age with a higher ASCVD risk   d. Low-dose aspirin might be reasonable for adults > 18 years of age with comorbid diabetes 

5. Which of the following is a limitation of the ARRIVE trial? a. Low incidence of gastrointestinal bleeding and cardiovascular events  b. The study only included adults > 70 years of age   c. The study only included men  d. Patients were excluded if they had a higher risk of bleeding  6. Which of the following is a true statement regarding the results of the ASPREE trial? a. This trial found a statistically significant benefit in utilizing aspirin over placebo for the primary outcome of death from any cause, dementia, and persistent physical disabilities   b. This trial found a statistically significant benefit in utilizing aspirin over placebo for the secondary outcome of cardiovascular disease  c. This trial found a statistically significant increase in major hemorrhage in patients utilizing aspirin as compared to placebo  d. This trial found a statistically significant benefit in utilizing aspirin over placebo for the primary outcome of cardiovascular death

7. What comorbidity was the focus of the ASCEND trial? a. Smoking  b. Obesity  c. Cancer  d. Diabetes mellitus

8. Which of the following accurately represents the results of the primary safety outcome related to bleeding in the ASCEND, ARRIVE, & ASPREE trials when comparing aspirin to placebo? a. Statistically significant higher bleeding risk with aspirin  b. Statistically significant lower bleeding risk with aspirin  c. No difference in bleeding risk with aspirin vs. no aspirin therapy  d. Statistically significant higher gastrointestinal bleeding with aspirin but no difference in other types of bleeding between the two groups 

9. Which of the following reversible risk factors increases a patient’s risk for bleeding? a. Black race  b. Moderate cardiovascular risk  c. Adults > 70 years of age  d. BMI < 30 kg/m2   

10. Which of the following is a counseling point to tell patients to be aware of while taking aspirin? a. Notify your provider if you experience black tarry stools  b. Take 1 tablet by mouth three times daily  c. Take 1 tablet by mouth 30 minutes before food  d. May crush enteric-coated tablets in patients with gastrostomy tube (G-tube)