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Author: Stormi Gale, PharmD, BCPS

One of the most controversial topics to come out of the 2018 European Society of Cardiology Congress was the question as to whether aspirin has a role for primary prevention of cardiovascular disease (CVD). This remains common practice in the United States, despite questionable evidence to identify a population for whom the benefits outweigh the risks. The United States Preventative Services Task Force (USPSTF) recommends aspirin in patients ages 50 to 60 years with an atherosclerotic cardiovascular disease risk of 10% or greater.1 However, the 2016 ESC guidelines recommend against antiplatelet therapy in patients without CVD due to an increased risk of major bleeding (See table 1 for full comparison of guideline recommendations).2

 

Population

2016 USPSTF 2016 ESC 2018 ADA

Adults < 50 yr

Insufficient evidence to recommend

(Grade I)

Not recommended

(Class III LOE B)

Not recommended

(Grade C)

Adults 50-59 yr with ≥ 10% 10-year CVD risk* Low-dose aspirin

(Grade B)

May be considered in patients with increased cardiovascular risk and not at an increased risk of bleeding

(Grade C)

Adults 60-69 yr with ≥ 10% 10-yr CVD risk*

Based on patient-specific risk/benefit

(Grade C)

Adults ≥ 70 yr

Insufficient evidence to recommend

(Grade I)

ADA, American Diabetes Association; CVD, cardiovascular disease; ESC, European Society of Cardiology; LOE, level of evidence; USPSTF, United States Preventative Services Task Force; *Patients must not be at increased risk for bleeding and must have a  life expectancy ≥ 10 yr and be willing to take low-dose aspirin daily for ≥ 10 yr


ARRIVE
The ARRIVE (Aspirin to Reduce Risk of Initial Vascular Events) study aimed to evaluate the efficacy and safety of low-dose aspirin at reducing major adverse cardiac events (MACE) in patients at moderate risk for CVD.4 Moderate risk was defined as a 10-year coronary heart disease (CHD) risk between 10 and 20 percent. Patients with diabetes were excluded. After a median follow-up of 60 months, there was no difference in the primary endpoint of cardiovascular (CV) death, myocardial infarction (MI), unstable angina, stroke, or transient ischemic attack (TIA) between aspirin and placebo. There was an increase in gastrointestinal bleeding (GIB) in the aspirin group (0.97% vs. 0.46%; HR 2.11; CI 1.36–3.28; p=0.007), although the majority of bleeding was mild.

At first glance, it seems obvious that there would be a lack of benefit with aspirin in this population. The transformed event rate in this study was low (less than 10% over 10 years despite the American College of Cardiology/American Heart Association risk stratification system estimating a 17.3% risk at baseline). ARRIVE does indeed tell us that these patients do not benefit from aspirin for primary prevention, but does this truly represent a “moderate-risk” population? Based on the event rate (and likely a result of the improved risk-modification with current medical therapy), the patients enrolled might in reality be considered “low-risk” – one of the few groups of patients that consistently are not considered eligible for aspirin according to various guidelines.

Another limitation of this study is the high rates of discontinuation of the study drug, which may explain the lack of benefit in preventing MI in the intention-to-treat protocol, despite significant benefit in the per-protocol analysis. The reduction of MI seen in the per-protocol analysis aligns more closely with benefits demonstrated in previous studies.1,5,6 Additionally, the per-protocol adverse events were not reported, so it is difficult to assess the corresponding risks in this portion of the analysis.


ASPREE
The ASPREE (Aspirin in Reducing Events in the Elderly) publications further confirm the lack of utility (and potential harms) of using aspirin in lower risk populations.7–9 This study evaluated aspirin 100 mg versus placebo in patients at least 70 years of age (or ≥65 years of age among blacks and Hispanics in the United States) without any cardiovascular disease, dementia, or disabilities. There was no benefit in the composite primary outcome of death, dementia, or persistent physical disability with aspirin. There was also no difference in major adverse cardiac events. However, the aspirin group was associated with a higher rate of major hemorrhage (8.6 events per 1000 person-years with aspirin and 6.2 events per 1000 person-years with placebo; HR, 1.38; 95% CI, 1.18 to 1.62; P<0.001). Additionally, there was an increase in all-cause death with aspirin, which was primarily due to an increase in cancer-related death compared to placebo (3.1% versus 2.3%; HR, 1.31; 95% CI, 1.10 to 1.56). More research is needed to interpret and identify the underlying mechanisms for this finding.

While this trial has certainly gained attention, I am not certain that the results will radically change current recommendations. Our current USPSTF guidelines do not recommend aspirin in patients 70 years of age or older as previous meta-analyses suggest that the benefits do not outweigh the risks.6 If nothing else, this trial provides further evidence against its use in older individuals.


ASCEND
Unlike ARRIVE, the ASCEND (A Study of Cardiovascular Events in Diabetes) study aimed to evaluate the benefit of aspirin in patients with diabetes and no known CVD.10 Low-dose aspirin was found to reduce the primary outcome of MACE (defined as vascular death, MI, or stroke/TIA) compared to placebo (8.5% vs. 9.6%; HR 0.88; 95% CI, 0.79 to 0.97; P=0.01). However, aspirin was associated with a 29% relative increase in major bleeding (4.1% vs. 3.2%; HR 1.29; 95% CI, 1.09 to 1.52; P=0.003), suggesting that the benefits of primary prevention may be balanced by the risks.

It is important to consider the population that was enrolled in ASCEND and whether or not the results can be generalized to the patients in your practice. The mean age and HgbA1c of patients in the trial was 63 and 7.2%, respectively. Almost 1 in 4 patients were greater than 70 years of age, a population that is known to have bleeding risks that outweigh the benefits (and for which the harms were again demonstrated in ASPREE above). Almost half of patients enrolled were between the ages of 60 and 70, a population in which the USPSTF recommends weighing individualized risks and benefits. The results of ASCEND should not be extrapolated to patients with very poorly controlled diabetes (who are arguably at higher risk for vascular events). Indeed, it has been suggested that patients with poorly controlled diabetes may be less likely to respond to aspirin; however, this phenomenon remains controversial as some evidence suggests that the prevalence of resistance is similar between patients with and without diabetes.11 Can we conclusively say that a 50-year-old with HgbA1c 13% and no risk factors for bleeding would not benefit from aspirin? ASCEND confirms what we already suspected – aspirin may prevent vascular events but these risks could be outweighed by bleeding in specific populations. Now what we need to know is: 1) do patients who benefit exist and, if so, 2) how do we better identify who these patients are?

The authors of ASCEND appropriately describe the difficulty in weighing benefits and risks for aspirin in primary prevention as the severity of one vascular event may not confer the same significance as a bleeding event. This is especially true considering that almost half of the bleeding events experienced were gastrointestinal in nature while hematuria and epistaxis accounted for approximately 20% of the total bleeds. The incidence of fatal bleeding and hemorrhagic stroke were not different between aspirin and placebo.


Where do we go from here?
Amongst all of the uncertainty surrounding aspirin for primary prevention, a few things remain apparent to me:

  1. Aspirin is not for everyone (but is it for anyone?).
  2. There is a need for improved risk-stratification systems.
  3. More attention should be given to each patients’ individualized risk/benefit.
  4. In most patients with advanced age, the benefits appear to be outweighed by the risks.

Although I am not certain that the results of recent trials wildly contradict current guideline recommendations (other than needing improved risk scores to stratify benefits), I feel that the current practice in the United States does. At minimum, the discussion generated from these trials should cause clinicians to put more consideration into the decision to use aspirin for this indication. In my opinion, it is less important that the above studies lead to major guideline revisions, but rather realign common practices with current evidence.


Bottom Line
Aspirin is not benign and should not be used as primary prevention in all populations, even those who intuitively (and using current risk calculators) might be considered “at-risk” for CVD, and especially those with increased risks of bleeding (i.e. advanced age). The decision to use aspirin in this context should be based on individualized analysis of risks and benefits while emphasizing patient preference.

 

Stormi Gale, PharmD, BCPS

Dr. Gale is an assistant professor in the Department of Pharmacy Practice and Science at the University of Maryland School of Pharmacy, and practices as a clinical pharmacy specialist at the University of Maryland Medical Center in Baltimore, MD. Follow her on Twitter @stormigale.

References:

  1. Final Recommendation Statement: Aspirin Use to Prevent Cardiovascular Disease and Colorectal Cancer: Preventive Medication. U.S. Preventive Services Task Force. Available from: https://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/aspirin-to-prevent-cardiovascular-disease-and-cancer. Updated September 2017. Accessed September 2018.
  2. Piepoli MF, Hoes AW, Agewall S, et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical PracticeEuropean Heart Journal. 2016;37(29):2315-2381.
  3. Standards of Medical Care in Diabetes (2017). Standards of Medical Care in Diabetes-2017: Summary of Revisions. Diabetes Care 2018 Jan 41(Supplement 1): S4-S6. https://doi.org/10.2337/dc18-Srev01. Accessed September 2018.
  4. Gaziano JM, Brotons C, Coppolecchia R, et al. 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. The Lancet. August 2018.
  5. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet. 1998;351(9118):1755-1762..
  6. Dehmer SP, Maciosek MV, Flottemesch TJ, LaFrance AB, Whitlock EP. Aspirin for the Primary Prevention of Cardiovascular Disease and Colorectal Cancer: A Decision Analysis for the U.S. Preventive Services Task Force. Ann Intern Med. 2016;164(12):777-786.
  7. McNeil JJ, Wolfe R, Woods RL, et al. Effect of Aspirin on Cardiovascular Events and Bleeding in the Healthy Elderly. New England Journal of Medicine. 2018;0(0):null.
  8. McNeil JJ, Woods RL, Nelson MR, et al. Effect of Aspirin on Disability-free Survival in the Healthy Elderly. New England Journal of Medicine. 2018;0(0):null.
  9. McNeil JJ, Wolfe R, Woods RL, et al. Effect of Aspirin on Cardiovascular Events and Bleeding in the Healthy Elderly. New England Journal of Medicine. 2018;0(0):null.
  10. Effects of Aspirin for Primary Prevention in Persons with Diabetes Mellitus. New England Journal of Medicine. 2018;0(0):null.
  11. Tasdemir E, Toptas T, Demir C, Esen R, Atmaca M. Aspirin resistance in patients with type II diabetes mellitus. Ups J Med Sci. 2014;119(1):25-31.

 

Aspirin for Primary Prevention: Have We ARRIVEd at an Answer?

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