New Trial Data

 
Two of the three recently completed primary prevention trials of low-dose aspirin were presented at the European Society of Cardiology Congress in Munich and simultaneously published online on August 26th.1,2

A Study of Cardiovascular Events in Diabetes2 (ASCEND, funded by the British Heart Foundation) was performed to assess the efficacy and safety of enteric-coated aspirin 100 mg daily, as compared to placebo, in 15,480 adults who had diabetes mellitus without clinically apparent cardiovascular disease. The primary efficacy outcome was the first serious vascular event, i.e., nonfatal myocardial infarction, nonfatal stroke or transient ischaemic attack, or death from any vascular cause (excluding confirmed intracranial hemorrhage). During a mean follow-up of 7.4 years, serious vascular events occurred in a significantly lower percentage of participants in the aspirin group than in the placebo group (658 participants [8.5%] vs. 743 [9.6%]; rate ratio, 0.88; 95% CI, 0.79 to 0.97; P=0.01). In contrast, major bleeding events occurred in 314 participants (4.1%) in the aspirin group, as compared with 245 (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 and other extracranial bleeding. In contrast to previous primary prevention trials, there were high rates of use of other preventive strategies with the majority of ASCEND participants  taking statins (75%) and blood-pressure lowering drugs. However, near the end of the trial, only about one quarter of participants were receiving proton-pump inhibitors. In such contemporary context, 91 subjects with diabetes would need to be treated to avoid a serious vascular event over a period of 7.4 years, and 112 to cause a major bleeding event. These results are important because:

  • they establish that low-dose aspirin is effective in the prevention of first cardiovascular events in patients with diabetes, when added on top of currently available cardioprotective strategies;
  • they provide diabetes guideline committees long-overdue, high-quality evidence on the efficacy and safety of low-dose aspirin in this setting to support or revise current treatment recommendations.

The Aspirin to Reduce Risk of Initial Vascular Events study1 (ARRIVE, funded by Bayer) was designed to investigate the efficacy and safety of 100 mg enteric-coated aspirin daily versus placebo in reducing a composite outcome consisting of time to first occurrence of confirmed myocardial infarction, stroke, cardiovascular death, unstable angina, or transient ischaemic attack, in 12,546 subjects with a moderate estimated risk of a first cardiovascular event. (defined as 10 to 20% 10-year coronary heart disease, with the exclusion of patients with diabetes). Median follow-up was 5 years. In the intention-to-treat analysis, the primary endpoint occurred in 269 (4·3%) patients in the aspirin group versus 281 (4·5%) patients in the placebo group (hazard ratio [HR] 0·96; 95% confidence interval [CI] 0·81–1·13; p=0·6038). Gastrointestinal bleeding events occurred in 61 (1.0%) patients in the aspirin group versus 29 (0.5%) in the placebo group (HR 2·11; 95% CI 1·36–3·28; p=0·0007). When looking at the proportion of the individual components of the primary end-point in the two treatment arms, findings from ARRIVE are generally consistent with previous primary prevention studies that tended to show aspirin’s ability to lower the risk of a first non-fatal myocardial infarction without affecting the risk of total stroke or vascular mortality. However, it should be appreciated that ARRIVE is a largely underpowered study to detect a moderate treatment effect in a low-risk population. In the original sample size calculation, it was estimated that 1488 events would provide 91% power to detect a relative risk reduction of 15%, assuming a placebo event rate of 13.4%. The actually observed rate of vascular events was only about one third of the expected, most likely reflecting the limited predictive power of risk calculators as well as the increasing use and effectiveness of various risk management strategies during the past 10 years.

Neither ASCEND nor ARRIVE reported evidence of a chemopreventive effect of low-dose aspirin against gastrointestinal tract cancer during the scheduled treatment period; long-term follow-up of these secondary outcomes is planned.

The ASPirin in Reducing Events in the Elderly (ASPREE) trial is expected to be reported soon. It can be anticipated that the cardiovascular findings of ARRIVE, ASCEND and ASPREE will be integrated into the existing body of evidence on the efficacy and safety of low-dose aspirin in a primary prevention setting, as summarised by the Antithrombotic Trialists' collaborative meta-analysis of individual participant data from randomised trials.3

References

1. 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; published online Aug 26. http://dx.doi.org/10.1016/S0140-6736(18)31924-X.

2. The ASCEND Study Collaborative Group. Effects of aspirin for primary prevention in persons with diabetes mellitus. N Engl J Med 2018; published online Aug 26. DOI: 10.1056/NEJMoa1804988.

3. ATT Collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet, 373:1849-1860, 2009.