ARRIVE – a Contribution to the Mounting Case Against Widespread Use of Low-dose Aspirin in the Primary Prevention of Cardiovascular Events

– Insight into the ARRIVE trial, the results of which were presented at the European Society of Cardiology Congress, Munich, Germany, 25–29 August 2018

The value of aspirin in secondary prevention of recurrent cardiac events is well established;^1,2 however, there remains considerable debate about how aspirin should be employed in primary prevention.

The Study to assess the efficacy and safety of enteric-coated acetylsalicylic acid in patients at moderate risk of cardiovascular disease (ARRIVE) sought to examine the primary prevention role of aspirin in patients with moderate estimated risk of a cardiovascular event. This population was chosen specifically to bridge a knowledge gap – many existing trials have been conducted in particularly low- or high-risk populations, or post-event or procedure.

ARRIVE is a multi-centre study that was performed across seven countries in 12,546 patients, who received either 100 mg aspirin or placebo (1:1). Patients were aged 55 years (male) and 60 years (female) or older and were at moderate estimated risk of cardiovascular events, but with no prior history. Patients at high risk of gastrointestinal bleeding or other bleeding, or who had a diabetes diagnosis, were excluded from ARRIVE. Median follow-up was 60 months.³

The primary efficacy endpoint was a composite outcome of time to first occurrence of cardiovascular death, myocardial infarction, unstable angina, stroke, or transient ischaemic attack.³

In the study’s primary intention-to-treat population, the primary efficacy endpoint occurred similarly in both arms: 4.29% of patients receiving aspirin and 4.48% of those in the placebo group.

There were fewer overall cardiovascular events (550) observed than the study investigators predicted (1,480). There was no meaningful difference in incidence of components of the composite endpoint between aspirin and placebo, and no subgroup treatment differences were noted.

The investigators noted that in the per-protocol population, where patients were at least 60% adherent to treatment, there was a significant reduction in time to first myocardial infarction; however, caution was advised when interpreting these results. Gastrointestinal bleeding was generally mild in the ARRIVE study, and occurred in 0.97% of the aspirin group and 0.46% of the placebo group. Overall, adverse event incidence was similar in the two treatment arms.³

Although ARRIVE aimed to investigate efficacy in patients at moderate risk of cardiovascular events, the event rate was much lower than predicted. This may reflect the benefits of contemporary risk management strategies, and thus the patients may be representative of a relatively low-risk population.

The findings of ARRIVE are broadly reflective of other primary prevention assessments that have published data recently. The Study of cardiovascular events in diabetes (ASCEND) found that aspirin use prevented serious vascular events in patients who had diabetes, but was associated with major bleeding events. The investigators concluded that the absolute benefits of aspirin in these patients were counteracted by increased bleeding risk.⁴ The Aspirin in reducing events in the elderly (ASPREE) study found that the use of low-dose aspirin as a primary prevention strategy in older adults (65 years or older) led to a significantly greater bleeding risk and no meaningful reduction in risk of cardiovascular events than placebo.⁵

Evidence is mounting against the widespread use of low-dose aspirin in the primary prevention of cardiovascular events. While there will undoubtedly be circumstances under which aspirin will play a beneficial role in disease management, it is clear that its use should be a decision that is personalised to an individual patient’s needs.

References

1. Gargiulo G, Windecker S, Vranckx P, et al. A critical appraisal of aspirin in secondary prevention: Is less more? Circulation . 2016;134:1881–906.
2. Godley RW, Hernandez-Vila E. Aspirin for primary and secondary prevention of cardiovascular disease. Tex Heart Inst J. 2016;43:318–9.
3. 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.
4. ACEND Study Collaborative Group. Effects of aspirin for primary prevention in persons with diabetes mellitus. N Engl J Med. 2018. doi: 10.1056/NEJMoa1804988
5. 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. doi: 10.1056/NEJMoa1805819