No overall benefit of use of aspirin in primary prevention setting in diabetes patients and individuals with moderate CV risk
ESC 2018 - Munich
A randomized trial of aspirin versus placebo for primary cardiovascular prevention in 15,480 people with diabetes (ASCEND)
Presented at the ESC congress 2018 by: Prof Jane Armitage (Oxford, UK)
Aspirin to Reduce Risk of Initial Vascular Events): A Study to Assess the Efficacy and Safety of Aspirin in Patients at Moderate Risk of Cardiovascular Disease (ARRIVE)
Presented at the ESC congress 2018 by: Prof J Michael Gaziano (Boston, MA, USA)
The benefit of aspirin has been well established in secondary prevention in patients with CVD and most guidelines support the use of low-dose aspirin in this setting. However, efficacy and safety of aspirin in the primary prevention of CV events remains controversial. More specifically, diabetes patients are at increased risk of heart attacks and strokes, but it is unclear whether aspirin treatment can prevent a first CV event.
The ASCEND trial enrolled 15,480 diabetes patients with no history of CVD, who were randomized to either 100 mg aspirin or placebo (and to omega-3 fatty acid supplementation, discussed in another article). The primary outcome was serious vascular events (SVE), a composite of non-fatal myocardial infarction (MI), non-fatal stroke, TIA or CV death, and the safety outcome was major bleeding. Follow-up was >99% complete for morbidity and mortality.
The ARRIVE trial, a randomized, double-blind, placebo-controlled, primary-care based multicenter trial, examined the efficacy and safety of 100 mg aspirin vs placebo in 12,546 subjects with a moderate estimated risk of first acute CV event (20-30% 10-year CVD risk, 10-20% CHD risk) without known diabetes or CVD. The primary endpoint was time to first occurrence of a composite of CV death, Ml, unstable angina (UA), stroke and transient ischemic attack (TIA) and safety endpoints included bleeding events and incidence of adverse events.
- After a mean follow-up of 7.4 years, SVE was reduced in the aspirin group compared to the placebo group (event rate 8.5% vs. 9,6%, HR: 0.88, 95%CI:0.79-0.97, P=0.01). Components of the composite primary outcome did not differ significantly between treatment arms.
- Addition of revascularization to the primary outcome resulted in similar results (10.8% vs. 12.1%, HR: 0.88, 95%CI:0.80-0.97, P=0.01).
- Major bleeding was increased in the aspirin group vs placebo (4.1% vs. 3.2%, HR:1.29, 95%CI:1.09-1.52, P=0.003).
- Bleeding risk increased with increasing baseline 5-year risk of SVE. Observed effects per 5000 person years of aspirin by baseline vascular risk showed that the greater benefit (SVE and revascularization) was counterbalanced by risk (bleeding) especially in the risk categories (6 fewer SVE/revascularization events and 3 more bleeds in those with <5%, 5-year risk, 13 fewer SVE/revasc events and 9 more bleed in those with 5-10% risk, and 11 fewer SVE/revasc and 10 more bleeds at >10% risk).
- There was no effect of aspirin treatment on the risk of cancer.
- After a median follow-up of 60 months in individuals with a less than anticipated 10-year event rate of <9%, the intention-to-treat analysis showed no difference in the primary endpoint between the aspirin group vs placebo group (HR: 0.96, 95%CI: 0.81-1.13, P=0.60).
- In the per-protocol analysis, risk of first MI was reduced in the aspirin group by 47% (HR: 0.53, 95%CI: 0.36-0.79, P=0.0014), risk of first non-fatal MI was reduced by 45% (HR: 0.55, 95%CI:0.36-0.84, P=0.0056) and there was no effect for stroke.
- Gastrointestinal bleedings occurred in 61 (0.97%) individuals in the aspirin group vs 29 (0.46%) in the placebo group (HR 2.11; 95% CI: 1.36-3.28; P=0·0007). No difference in fatal bleeding rates was observed.
- No effects were observed in short-term cancer rates.
There was no netto CV benefit for use of aspirin in a primary prevention setting of diabetes patients or individuals with moderate CV risk. Although use of aspirin reduced SVE in diabetes patients, the CV benefit was counterbalanced by the increased risk of bleeding.
During the discussions of both presentations in the press conference, it was mentioned that the individuals in these trials were well controlled for risk factors and Professor J. Michael Gaziano, principal investigator of the ARRIVE trial, of the Brigham and Women's Hospital, Boston, US, said: “Aspirin did not reduce the occurrence of major cardiovascular events in this study. However, there were fewer events than expected, suggesting that this was in fact a low risk population. This may have been because some participants were taking medications to lower blood pressure and lipids, which protected them from disease.” Dr. Armitage also noted that the risk of patients in the ASCEND trial can get quite low with treatment with other medications; aspirin did not add to this.
The effect of cancer that had been seen in smaller, observational studies, was not confirmed in ASCEND. Patients enrolled in ASCEND will be followed at 5 and 10 years beyond the end of the study, to evaluate whether an increased risk of gastrointestinal cancer may appear at a later stage. In the currently studied period, no such effect was seen.
Part of the discussion was dedicated to the differences seen between the intention-to-treat and per protocol analyses in the ARRIVE trial. Discontinuation of the study drug was seen over time (compliance rate in the per protocol analysis was 60%), and selective drop-in occurred as well. Gaziano said that in those who were not specifically selected for aspirin use (by their physician because they developed TIA, or risk), the results were more similar to what has been seen before.
In light of these neutral trial outcomes, it was concluded that overall the use of aspirin remains a decision that should involve a discussion between physicians and patients to weigh benefits and risks.
Results of the ARRIVE are published in The Lancet.
Results of the ASCEND are published in NEJM.
-Our reporting is based on the information provided at the ESC congress-