No benefit on mortality with use of aspirin in primary prevention setting
Efficacy and safety of aspirin for primary prevention of cardiovascular events: a meta-analysis and trial sequential analysis of randomized controlled trials
Introduction and methods
The use of aspirin for primary prevention of CV events is heavily debated, and recommendations in guidelines vary from advising against its use  to endorsing it in high-risk patients such as those with high CV risk  or diabetes . The recommendation for use of aspirin for primary prevention was based on a pooled analysis of six randomized trials in which a reduction of ischemic events was observed with aspirin use .
Aspirin is still commonly used among healthy individuals without established atherosclerosis, hoping that it will prevent myocardial infarction (MI) and death. However, conflicting data have been published on the benefit and safety of aspirin for primary prevention [5,6]. A recent meta-analysis  showed a reduction on non-fatal MI, but little or no effect on CV or all-cause mortality of aspirin in a primary prevention setting. These analyses, however, comprised several trials that included patients with known atherosclerosis and peripheral vascular disease [7,8]. The impact of this heterogeneity in the patient population is unclear.
Since recently the results of several large-scale randomized trials have been reported, this is an updated meta-analysis and trial sequential analysis of randomized trials to evaluate the efficacy and safety of aspirin in patients without prior known history of atherosclerotic CV disease. The primary efficacy outcome was all-cause mortality, and primary safety outcome was major bleeding. 11 Studies encompassing data on 157.248 participants met inclusion criteria. Two trials included 5-6% of patients with prior history of heart disease. These studies were included in the main analysis, but a sensitivity analysis that excluded them was performed. Overall weighted mean follow-up duration was 6.6 years (SD: 0.7 years). A secondary analysis was conducted using hazard ratios (HRs) to account for the variation in follow-up between studies and to asses the impact of censoring.
- The incidence of all-cause mortality did not differ significantly between the aspirin and control groups (4.6% [95%CI: 3.4-5.8%] vs. 4.7% [95%CI: 3.6-5.9], RR: 0.98, 95%CI: 0.93-1.02, P=0.30, I²=0%).
- The secondary analysis based on HRs showed a similar result for all-cause mortality (HR: 0.98, 95%CI: 0.93-1.04, P=0.51, I²=17%).
- The effect did not change when two non-placebo controlled trials were excluded (HR: 0.99, 95%CI: 0.93-1.05, P=0.68, I²=22%) or when the trials with a minority of patients with known CVD were excluded (RR: 0.99, 95%CI: 0.94-1.04, P=0.63, I²=6.6%).
- No evidence was found for interaction with the effect of aspirin on mortality of 10-years risk, diabetes, mid-enrolment year, aspirin dose, risk of bias and follow-up duration.
- No significant differences were seen in the secondary efficacy outcomes of CV mortality or ischemic stroke. MI showed a lower incidence with aspirin (1.9% vs. 2.2%, RR: 0.82, 95%CI: 0.71-0.94, P=0.006), but the degree of heterogeneity was large (I²=67%) between trials.
- A higher incidence of major bleeding was seen with aspirin (1.8% [95%CI: 1.3-3.4%] vs. 1.2% [95%CI: 0.8-1.6%], RR: 1.47, 95%CI: 1.31-1.65, P<0.0001, I²=31%). (NNH=250).
- The secondary analysis showed a similarly increased risk of major bleeding (HR: 1.47, 95%CI: 1.31-1.64, P<0.0001, I²=30%), nor did the finding change after exclusion of the non-placebo controlled trials and the trials with a minority of patients with a history of CVD.
- The incidence of intracranial hemorrhage was higher with aspirin (0.4% [95%CI: 0.2-0.5%] vs. 0.3% [95%CI: 0.1-0.4%], RR: 1.33, 955CI: 1.13-1.58, P=0.001, I²=0%) (NNH=1000).
- Trial sequential analysis confirmed the finding that there is a lack of benefit from aspirin on all-cause mortality, and that future trials are not useful for further evaluation of this effect
In this meta-analysis, aspirin was not associated with a reduction in the risk of all-cause mortality in the primary prevention setting, also in diabetic patients and patients with high CV risk. Aspirin was, however, associated with an increase in major bleeding and intracranial hemorrhage. Thus, this analysis confirm the lack of overall benefit from routine aspirin use in the setting of primary prevention. Moreover, a trial sequential analysis suggested the futility of conducting further trials to assess a benefit of aspirin on all-cause mortality.
Valgimigli predicts in his editorial  that 2018 may be remembered as the year when aspirin, about 121 years old, came of age. He notes that while aspirin remains the cornerstone treatment for secondary prevention in patients with established CVD, three large recent high-quality randomized controlled trials now question the somewhat liberal use of aspirin that has been recommended by some guidelines. The current meta-analysis included these last trials and shows no signal of any treatment effect of aspirin on mortality, CV mortality or stroke, while the risk of major bleeding and intracranial bleeding was increased.
About the lower risk of MI he wonders whether trading a single MI for bleeding would be an acceptable option. The comparative prognostic implications of the two events have been investigated, and unsurprisingly, the outcomes depend on the severity of bleeding. But, Valgimigli notes, ‘the key upstream question remains of whether the effect of aspirin on MI prevention is real and reproducible in contemporary practice’, considering the large heterogeneity between studies. Moreover, he describes that when plotting the use of statins and the relative risk reduction for MI across the included study, an association emerges between no or minimal use of statins and greater absolute effect of aspirin on MI prevention. Other studies point in the same direction, and ‘taken together, current evidence raises concerns that aspirin can significantly contribute to MI prevention in patients when properly treated with lipid-lowering agents as per todays’ practice and guidelines.’
The use of routine antiplatelet agents other than aspirin in high-risk patients for primary prevention remains unclear, as well as how to manage patients fulfilling the 1.5 prevention setting, thus those with established atherosclerotic disease but no ischemic event yet or development of symptoms. The THERMIS study is currently studying the efficacy and safety of ticagrelor as a means to avoid the consequences of plaque rupture in patients who may have ongoing yet asymptomatic plaque rupture episodes. Valgimigli concludes: ‘Meanwhile, we should get ready to say a farewell to aspirin even in asymptomatic patients in whom an atherosclerosis disorder is not established, irrespective of the anticipated risk of future ischaemic events or concomitant cardiovascular risk factors.’
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