The role of aspirin for the primary prevention of cardiovascular disease in individuals with chronic kidney disease

This editorial refers to ‘Aspirin for the primary prevention of cardiovascular disease in individuals with chronic kidney disease: a systematic review and meta-analysis’, by S. Pallikadavath et al., pp. 1953–1960. Aspirin is well established and widely used for secondary prevention of atherosclerotic cardiovascular disease (ASCVD) and is currently recommended for this indication in most practice guidelines.1,2 However, in the absence of robust evidence, aspirin has been widely used by individuals without a history of ASCVD.3 Several recent clinical trials evaluating the efficacy of aspirin in primary prevention of ASCVD could demonstrate that the risk of aspirin may outweigh the benefit in the majority of individuals. This led to more restrictive recommendations for aspirin use and a large proportion of subjects previously thought to benefit from aspirin are currently no candidates any more. Low-dose (75–100 mg per day) aspirin might be considered for the primary prevention of ASCVD only among selected adults 40–70 years of age who are at higher ASCVD risk but not at increased bleeding risk. Additionally, in adults over 70 years of age aspirin should not be administered on a routine basis for the primary prevention of ASCVD and finally, aspirin should not be prescribed for the primary prevention of ASCVD among adults of any age who are at increased risk of bleeding including those with a history of gastrointestinal bleeding, major bleeding from other sites, age over 70 years, thrombocytopenia, coagulopathy, concurrent use of non-steroidal anti-inflammatory drugs and anticoagulants, and chronic kidney disease (CKD).4 A large number of studies have shown beneficial effects of statins, blood pressure reduction, glucose-lowering drugs, and additional multi-factorial lifestyle intervention in reducing the risk of cardiovascular (CV) events among patients with diabetes.5–7 However, although the incidence of CV events declined substantially over the last two decades among individuals with diabetes, this metabolic disease is remaining to be associated with an excess risk of fatal and non-fatal CV outcomes as compared with the general population.8 The increased residual CV risk of diabetic subjects could suggest that aspirin might be beneficial when used for primary prevention of ASCVD.9 However, recent clinical trials including the Antithrombotic trialists’ collaboration, ASCEND, ARRIVE, and ASPREE10–13 suggest that despite aspirin appears to have a modest impact on decreasing ischaemic CV events (in particular in individuals with higher ASCVD risk), this benefit is tempered by increased bleeding events (mostly gastrointestinal bleeds). In diabetic people, with an estimated ASCVD risk of more than 1% per year the number of ASCVD events that are averted are comparable to the number of bleeding events caused. However, it has to be recognized that ASCVD events including CV death, myocardial infarction, and stroke and (gastrointestinal) bleeding events do not have equal long-term effects on quality of life and overall health.14 Diabetic individuals over 50 years of age with at least one additional ASCVD risk factor (elevated blood pressure, hypercholesterolaemia, current smoking, family history of ASCVD, CKD) and without increased bleeding risk (anaemia, impaired renal function, history of major bleeding, advanced age beyond 70 years) are most likely to benefit from aspirin for primary prevention of ASCVD. Considering the narrow line between benefit and harm, a comprehensive discussion with the patient is warranted.14 Similarly to patients with diabetes, people with CKD are at an increased risk of ASCVD events15 and aspirin might be beneficial when used for primary prevention. The study by Pallikadavath et al.16 published in this issue of the Journal assessed risks and benefits of aspirin in the primary prevention of ASCVD in individuals with CKD. The authors performed a systematic review and meta-analysis that included five randomized controlled clinical trials published within the last 6 years which assessed aspirin vs. placebo in adults with non-endstage CKD without a previous diagnosis of CVD. A total of 7852 individuals were included in the analyses (3935 on aspirin and 3917 on placebo). The primary endpoint was ASCVD events. Secondary endpoints included all-cause mortality, coronary heart disease (CHD), stroke, and major and minor bleeding events. The analyses are based on a total of 434 primary endpoint events. The authors found that aspirin treatment was not associated with a statistically significant reduction of ASCVD events [hazard ratio (HR) 0.76, 95% confidence interval (CI) 0.54–1.08, P = 0.13]. For the primary outcome, the percentage of variation in study outcomes across studies that is due to heterogeneity rather than chance for the primary outcome (I2) was 63%. Aspirin when compared to placebo was associated with a HR of 0.94 (95% CI 0.74–1.19, P = 0.60, I2 = 21%) for all-cause mortality, 0.66 (95% CI 0.27–1.63, P = 0.37, I2 = 64%) for CHD events, and a HR of 0.87 (95% CI 0.6–1.27, P = 0.48, I2 = 24%) for stroke. As expected, aspirin treatment led to a statistically significant increased risk of bleeding events with a HR of 1.53, 95% CI 1.13–2.05, P = 0.01, I2 = 0% for major bleeding events and a HR of 2.64, 95% CI 1.64–4.23, P < 0.01, I2 = 0% for minor bleeding events. Remarkably, while substantial heterogeneity could be detected for ASCVD events, an increased risk of bleeding events was consistent across studies. Based on the results the authors conclude that aspirin cannot be routinely recommended for the primary prevention of ASCVD events in individuals with CKD as there is no evidence for its benefit but there is an increased risk of bleeding. Pallikadavath et al. have to be congratulated for elucidating this issue. However, several methodological issues and limitations have to be addressed: First, the majority of studies included in this analysis used a single assessment of eGFR to categorize individuals as CKD. This might have resulted in misclassification and could have introduced error.17–19 Additionally, the stage of kidney disease might influence the balance between benefit and harm with a lower risk of bleeding events and a more favourable risk–benefit ratio with aspirin in CKD patients with only mild renal impairment.20 Second, this review was conducted as an aggregate data meta-analysis. The authors had no access to individual patient data that might have allowed improved patient characterization regarding the degree of renal dysfunction and in-depth assessment of heterogeneity across studies observed in these analyses. Third, the authors report that ASCVD events were reduced by 24% and CHD events were reduced by 34%. Both estimates did not turn out to be statistically significant. However, based on 434 primary endpoint events only, this meta-analysis might be under-powered and a clinically meaningful reduction of ASCVD risk with aspirin cannot be excluded. Thus, further data are required to confirm or refute the conclusion of the present meta-analysis. Several studies investigating the scientific question of the role of aspirin for the primary prevention of ASCVD in individuals with CKD were summarized by Major et al. previously. The conclusion was that aspirin is associated with a statistically significant higher risk of bleeding. However, the evidence of a reduced risk of ASCVD events was deemed inconclusive.21 The current review16 which included recently published randomized trials did not substantially change this conclusions (Figure. 1). Aspirin and primary prevention in CKD patients. As mentioned above, the presence of CKD per se indicates increased bleeding risk22 and has been added to the list of parameters that are used to estimate the risk–benefit ratio for the use of antithrombotic agents in individuals at high risk of ASCVD events.4 Thus, the line between benefit and harm of aspirin treatment for primary prevention in CKD patients may be even narrower when compared to the general population and even to people with diabetes. The risk–benefit ratio of aspirin in primary prevention of patients with CKD is modified by the degree of renal dysfunction with less net clinical benefit or even harm in patients with moderate to severe renal impairment.23 The estimation of the benefit–harm ratio for prescription of aspirin in individuals with CKD based on clinical characteristics only may result in misclassification. Thus, additional tools including non-invasive imaging techniques (e.g. coronary artery calcium score) could potentially help to identify people (including individuals with CKD) for aspirin primary prevention therapy.24 Based on the evidence currently available aspirin cannot be recommended for the primary prevention of ASCVD events in individuals with CKD on a routine base. Prioritization should be given to controlling CV risk factors, such as hypertension, dyslipidaemia, diabetes, and smoking.25 However, refinement in the estimation of the individual risk–benefit ratio by adding non-invasive imaging techniques to clinical characteristics may help to select appropriate CKD patients for aspirin primary prevention therapy. Conflict of interest: none declared. The opinions expressed in this article are not necessarily those of the Editors of the European Journal of Preventive Cardiology or of the European Society of Cardiology.