"It's not you, it's me" is the classic relationship breakup adage used to try to soften the blow of the breakup and indicate that it's not the fault of the person being broken up with. With three recent large randomized trials studying aspirin for primary prevention of cardiovascular disease (CVD) showing no or only modest benefit (Table 1), the question has been appropriately raised if it is time to end our relationship with aspirin for primary prevention. Aspirin has been one of the mainstays of CVD prevention across the globe for decades. Before any decisions are made about this important and complex topic, it is important to understand the details of the recent trials and how they fit in the context of the prior aspirin research.

Table 1: Summary of the Three Aspirin Trials for Primary Prevention of Cardiovascular Disease

	ARRIVE	ASCEND	ASPREE
Sample Size	12,546	15,480	19,114
Inclusion Criteria	Multiple risk factors without established CVD	Diabetes without established CVD	Age ≥ 70 years without established CVD
Mean Age	64 years	63 years	74 years
Mean Follow-up	5 years	7.4 years	4.7 years
Aspirin Dose	100 mg	100 mg	100 mg
Ratio for CVD Benefit	0.96 (95% CI 0.81-1.13)	0.88 (95% CI 0.79-0.97)	0.95 (95% CI 0.83-1.08)
Bleeding Risk	2.11 (95% CI 1.36-3.28)	1.29 (95% CI 1.09-1.52)	1.38 (95% CI 1.18-1.62)

In the 1980s and 90s, multiple randomized trials established aspirin as an effective tool to reduce the risk of myocardial infarction and stroke in populations with and without established CVD, but subsequent primary prevention trials in the early 200's were not able to confirm the benefit of aspirin for primary prevention.¹ This lack of clarity led to calls for additional data and three new trials were published in 2018, aiming to definitively determine the benefit of aspirin for primary prevention in modern populations.

A Study of Cardiovascular Events in Diabetes (ASCEND) randomized 15,480 adults with diabetes but without established CVD to 100 mg of aspirin or placebo.² The ASCEND trial demonstrated a small benefit with use of aspirin. During a mean follow-up of 7.4 years, serious vascular events occurred were significantly lower on aspirin (8.5% vs. 9.6%; rate ratio, 0.88; 95% confidence interval [CI], 0.79 to 0.97; P = 0.01). In contrast, major bleeding events occurred in 4.1% of the aspirin group, compared with 3.2% in the placebo group (rate ratio, 1.29; 95% CI, 1.09 to 1.52; P = 0.003), with most of the excess being gastrointestinal bleeding.

The Aspirin for Reducing Events in the Elderly (ASPREE) trial studied the benefit of aspirin in an elderly population free of CVD, randomizing 19,114 individuals age 70 years and older without cardiovascular disease to 100 mg of aspirin or placebo.³ After a median of 4.7 years of follow-up, there was no significant difference in the rate of major CVD events (hazard ratio, 0.95; 95% confidence interval [CI], 0.83 to 1.08) but there was an increase in the rate of major hemorrhage (8.6 events per 1000 person-years on aspirin vs 6.2 events per 1000 person-years on placebo, HR 1.38; 95% CI, 1.18 to 1.62; P < 0.001). Additionally, ASPREE analyzed the effect of aspirin on all-cause mortality and surprisingly found an increase in all-cause mortality in individuals randomized to aspirin (HR 1.14; 95% CI 1.01 to 1.29).⁴ The increase in mortality was largely driven by an increase in cancer deaths, a finding that counters prior aspirin data that suggested a reduction in cancer risk with aspirin (specifically colorectal cancer), and therefore should be interpreted with caution.

Finally, the Aspirin to Reduce the Risks of Initial Vascular Events (ARRIVE) trial intended to study a population at moderate risk for CVD (mean estimated 10-year atherosclerotic CVD risk was ~17%) and randomized 12,546 adults (men ≥55 years, women ≥60 years) to aspirin 100mg or placebo.⁵ Over 5 years of follow-up, CVD event rates were not significantly different between the two groups (HR 0·96; 95% CI 0·81–1·13; p = 0·60). Gastrointestinal bleeding events (mostly mild) occurred in 61 (0·97%) patients in the aspirin group versus 29 (0·46%) in the placebo group (HR 2·11; 95% CI 1·36–3·28; p = 0.0007). The authors note that though they targeted a population at moderate risk, the study population was more representative of a low-risk population, with 5-year CVD event rates <5% in both arms.

The recently released 2019 American College of Cardiology/American Heart Association Guideline on the Primary prevention of Cardiovascular Disease includes recommendations on the use of aspirin for primary prevention of CVD.⁶ Based largely on the results of the three recent trials, the committee gave a class III: Harm recommendation for use of aspirin for primary prevention in patients ≥70 years old as well as in individuals at increased risk of bleeding such as those on oral anticoagulants or a history of a prior bleeding episode. For adults age 40-70 years old, the guidelines give a class IIb recommendation that aspirin may be considered for primary prevention in those who are at higher CVD risk and not at increased bleeding risk.

Reconciling the declining benefit of aspirin for primary prevention can likely be largely explained by three key factors. First, decreases in population rates of CVD, especially myocardial infarction,⁷ have contributed to limiting the benefit of aspirin in recent trials. With improved control of blood pressure and cholesterol and lower rates of smoking in modern populations, it is difficult to identify high-risk primary prevention patients. In ARRIVE, despite the sample having multiple risk factors and an estimated 10-year risk of ~17%, the event rates were more consistent with a low risk population, leaving little room for aspirin to achieve a significant benefit.⁵ Second, a change in reported outcomes has likely contributed the decline in benefit. The main reported outcome for the aspirin component of the Physician's Health Study was myocardial infarction, which was reduced by 44%.⁸ The recent trials have primary outcomes that are composites of total CVD, including CVD death. There are multiple different mechanisms that could lead to CVD death that are not atherothrombotic in etiology (heart failure, dissection, arrhythmia, etc.) and therefore unlikely to be affected by aspirin. Finally, with studies that require long duration of follow-up, an intention to treat analysis does come with a risk of bias towards a null result. In ARRIVE, in the intention to treat analysis there was no significant reduction in myocardial infarction (HR 0.85 [95% CI 0.64-1.11]). However, approximately 30% of ARRIVE participants terminated the study prematurely. In the per-protocol analysis, including only those who remained on their assigned treatment for the duration of the study, there was a 47% reduction in myocardial infarction (p-value 0.0014) with use of aspirin.⁵

In summary, the three recent trials have confirmed the notion that the benefit of aspirin in modern primary prevention populations is small and for most individuals is probably not worth the risk in bleeding. However, for individuals who are at elevated CVD risk and low risk of bleeding, consideration for use of aspirin is reasonable and should be discussed in the context of shared decision making between the patient and their provider. Should we break up with aspirin for primary prevention? For many of us, the answer is yes, but we should understand that it isn't aspirin that's changed, we have.

References

1. Miedema MD, Huguelet J, Virani SS. Aspirin for the primary prevention of cardiovascular disease: in need of clarity. Cirr Atheroscler Rep 2016;18:4.
2. ASCEND Study Collaborative Group, Bowman L, Mafham M, et al. Effects of aspirin for primary prevention in persons with diabetes mellitus. N Engl J Med 2018;379:1529-39.
3. McNeil JJ, Wolfe R, Woods RL, et al. Effect of aspirin on cardiovascular events and bleeding in the healthy elderly. N Engl J Med 2018;379:1509-18.
4. McNeil JJ, Nelson MR, Woods RL, et al. Effect of aspirin on all-cause mortality in the healthy elderly. N Engl J Med 2018;379:1519-28.
5. 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. Lancet 2018;392:1036-46.
6. Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2019. [Epub ahead of print]
7. Yeh RW, Sidney S, Chandra M, Sorel M, Selby JV, Go AS. Population trends in the incidence and outcomes of acute myocardial infarction. N Engl J Med 2010;362:2155-65.
8. Steering Committee of the Physicians' Health Study Research Group. Final report on the aspirin component of the ongoing Physicians' Health Study. N Engl J Med 1989;321:129-35.

Keywords: ACC Annual Scientific Session, ACC19, Aspirin, Risk Factors, Risk Factors, Blood Pressure, Factor XII, Intention to Treat Analysis, Hemorrhage, Primary Prevention, Stroke, Myocardial Infarction, Anticoagulants, Cholesterol, Heart Failure, Diabetes Mellitus, Arrhythmias, Cardiac, Colorectal Neoplasms, Smoking

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