# Eligibility of real-world patients for aspirin primary prevention trials in cardiovascular disease

## TL;DR

This study shows that most real-world patients don't meet the criteria of aspirin prevention trials, suggesting trial results may not apply broadly.

## Contribution

The study applies RCT eligibility criteria to real-world data to assess external validity of aspirin trial results for CVD prevention.

## Key findings

- Most patients (median 90.7%) were ineligible for aspirin RCTs, with many excluded from all trials.
- Trial-ineligible patients were younger and had lower rates of hypertension and diabetes compared to eligible patients.
- Trial-ineligible populations showed varied risks for MACE, bleeding, and non-CVD death compared to eligible groups.

## Abstract

Evidence for the net benefit of aspirin for primary prevention of cardiovascular disease (CVD) is finely balanced, leading to variation in guideline recommendations internationally. External validity of randomised clinical trial (RCT) evidence may therefore be of particular importance. The aim of this study is to characterise real-world patients according to their eligibility for guideline-cited aspirin RCTs for primary CVD prevention.

Eligibility criteria from 14 RCTs were applied to a linked primary care/hospital discharge dataset of people ≥ 40 years without CVD. Proportions eligible for each trial were calculated, and characteristics of eligible and ineligible patients compared for each trial, including Cox regression analysis of event rates for major adverse cardiovascular events (MACE), major bleeding events, and non-cardiovascular mortality.

Of 570,211 included patients (300,500 [52.7%] women, 336,877 [59%] < 60 years), the median proportion ineligible for 14 RCTs was 90.7% (range 42.5–99.4%) and 24.0% of patients were ineligible for all RCTs. On average, trial-ineligible populations were younger (median age trial-ineligible 57.8 vs trial-eligible 62.6 years, p = 0.008) and a lower proportion had hypertension (23.9% vs 50.9%, p = 0.004), diabetes (6.4% vs 11.5%, p = 0.015), or a regular statin prescription (11.8% vs 26.7%, p = 0.001). Trial-ineligible populations had a higher hazard of MACE compared to trial-eligible in four RCTs and lower in ten (hazard ratio [HR] range across all RCTs 0.45 [95%CI 0.40–0.51] to 2.78 [95%CI 2.61–2.96]). Hazards of bleeding events in the trial-ineligible were lower than the trial-eligible in eight RCTs and higher in four (HR range across all RCTs 0.63 [95%CI, 0.59–0.66] to 1.69 [95%CI, 1.53–1.86]), and time-varying hazards of non-CVD death were consistently lower in four RCTs and higher in five (HR range across all RCTs and time points 0.29 [95%CI 0.24–0.36] to 11.42 [95%CI 9.91–13.17]).

Compared with trial-ineligible populations within the same age and sex strata, RCTs recruited people of varying CVD risk but often excluded people at high risk of bleeding or non-CVD death, highlighting that many trials may overestimate the net benefit of aspirin for primary prevention.

The online version contains supplementary material available at 10.1186/s12916-026-04654-w.