"It's Not You, It's Me" - Is it Time to Break Up With Aspirin?

Michael D. Miedema, MD; Thomas Knickelbine, MD, FACC


July 25, 2019

This article is republished with permission from the ACC. For more, see www.ACC.org.

"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.

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.