Reference: N Engl J Med. 2018;379(16):1499-1508 (level 2 [mid-level] evidence)
Cardiovascular disease is the leading cause of death worldwide, accounting for over 17.6 million deaths in 2016 (Circulation. 2019 Mar 5). Physicians and patients alike strongly desire to prevent heart attack and stroke, leading many patients to take a daily aspirin. However, the degree or even presence of benefit of aspirin for primary prevention varies by population and has risk of adverse reactions, ranging from gastrointestinal upset to severe bleeding events (Ann Intern Med. 2019 Oct 15, N Engl J Med 2018, Cochrane Database Syst Rev. 2011 Dec 7). For primary prevention of cardiovascular disease, does the benefit of aspirin outweigh the risks for most adults? The study to be reviewed aims to answer this question, assessing the efficacy and safety of aspirin in adults with moderate risk of cardiovascular disease.
The Aspirin Risk Reduction In Vascular Events (ARRIVE) trial was a randomized, double blinded, placebo-controlled study that compared the efficacy of enteric-coated aspirin 100 mg once daily vs. placebo in 12,546 adults (aged ≥ 55 years if male or ≥ 60 years old if female [mean age 63 years, 70% men]) with moderate cardiovascular risk. Moderate cardiovascular risk was defined as having a number of the following risk factors (2-4 in men and ≥ 3 in women): hypercholesterolemia (in men, total cholesterol > 200 mg/dL or low-density lipoprotein [LDL] > 130 mg/dL; in women, total cholesterol > 240 mg/dL or LDL > 160 mg/dL), high-density lipoprotein (HDL) < 40 mg/dL, smoking within the past year, systolic blood pressure > 140 mm Hg, receiving anti-hypertensive medications, and/or family history of cardiovascular disease. Patients were excluded if they had high bleeding risk (history of gastric or duodenal ulcers or gastrointestinal bleeding, and those requiring concomitant use of anticoagulants or frequent use of non-steroidal anti-inflammatory drugs), previous vascular events, or were diabetic. Due to lower than expected event rates, the study protocol was amended to include more outcomes in the primary composite outcome and follow-up was extended by 12 months. The primary outcome was a composite of time to first occurrence of cardiovascular death, myocardial infarction, stroke, unstable angina, and transient ischemic attack. Median follow-up was 60 months. 27% of patients discontinued the trial, and all patients were included in the analyses.
When comparing aspirin vs. placebo, there were no significant differences in the primary outcome, occurring in 4.29% vs. 4.48% (or any individual component of the primary outcome), or all-cause mortality, occurring in 2.55% vs. 2.57%. Gastrointestinal bleeding (any) occurred in 0.97% with aspirin vs. 0.46% with placebo (p = 0.0007, number needed to harm [NNH] of 196). Rates of fatal bleeding events were not significantly increased with aspirin. Treatment-related adverse events occurred in 16.75% with aspirin vs. 13.54% with placebo (p= < 0.0001, NNH 31). The most common (≥ 1%) treatment-related adverse events reported were dyspepsia, epistaxis, gastroesophageal reflux disease, and upper abdominal pain.
The ARRIVE trial adds to a growing body of recent evidence demonstrating a lack of benefit of aspirin for preventing primary cardiovascular events and increased risk of non-fatal gastrointestinal bleeding events Clinicians should engage patients in shared decision making when it comes to prescribing aspirin for primary prevention (Lancet. 2018 Sep 22).
For more information, see the topic Aspirin for Primary Prevention of Cardiovascular Disease in DynaMed.
Sara Dusing is from Martinsburg, West Virginia and is a recent graduate of the family medicine residency program at the University of Virginia and is now in private practice close to her hometown in West Virginia.
Faculty contributions by Dr. Katharine DeGeorge