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Study Summary

The multicenter ARRIVE trial aimed to test the efficacy of aspirin for the primary prevention of cardiovascular events in a moderate-risk, US and European population. Patients were randomized to receive 100 mg enteric-coated aspirin or placebo once daily (N = 12,546). Men aged ≥ 55 years with 2-4 cardiovascular risk factors, or women aged ≥ 60 years with ≥3 risk factors were included. Diabetics, and patients with prior vascular events or gastrointestinal bleeding were excluded. Baseline characteristics between groups were similar. Over a mean follow-up of 5 years, the intention-to-treat analysis showed no significant difference (aspirin 4.29% vs. placebo 4.48%, P = 0.6) in the composite primary endpoint (cardiovascular death, myocardial infarction, unstable angina, stroke, or transient ischemic attack; see accompanying Hurst’s Central Illustration) and higher rates of gastrointestinal bleeding with aspirin (0.97% vs. 0.46% P = 0.0007). No difference was seen in the individual components of the composite endpoint or for specific subgroups for any study endpoint. The rate of fatal or non-fatal myocardial infarction was lower with aspirin in the per-protocol analysis (0.98% vs. 1.84%, P = 0.0014).

Commentary

Study Strengths: This was a large trial carried out in 501 centers across seven countries (>90% enrolled in Poland, Germany, or the UK). Women and older patients were well represented in the study population. Many patients were on appropriate and contemporary medications to reduce cardiovascular risk (e.g. statins).

Study Limitations: The mean ACC/AHA 10-year estimated ASCVD risk score in both groups was >17%, but observed event rates in the trial were considerably lower than expected (10-year event rate: 8.43% aspirin vs. 8.8% placebo) suggesting that the study cohort represented a lower-risk population. Lower than expected event rates could reflect both overestimation of risk with current risk calculators, as well as efficacy of concomitant medical therapy aimed at reducing cardiovascular risk. Notably, enteric-coated aspirin was used in this study, which may inhibit aspirin pharmacokinetics. There was a high rate of premature termination of the study (>1800 subjects in both groups). Finally, per-protocol analyses should be interpreted with caution as no data for treatment cross-over is presented and protocol adherence data relied solely on patient report.

Next Steps/Clinical Perspective: The study highlights the need to re-evaluate current methods of estimating cardiovascular risk to reflect contemporary risk factors and incorporate the influence of contemporary medical therapy. The per-protocol analysis suggests that there is a population in whom aspirin may be helpful to prevent myocardial infarction, thus use of aspirin for primary prevention should remain a case-by-case decision based on the patient’s individual risk.

Trial Reference

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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 doi: 10.1016/S0140-6736(18)31924-X

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