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4.9.1. Antithrombotic therapy in individuals without atherosclerotic disease In 2009, a meta-analysis in patients with low CVD risk reported a 12% reduction in ASCVD with aspirin but a significant increase in major bleeding.619 CVD risk reduction and bleeding risks were similar in men and women.631 More contemporary primary prevention trials reported no or little benefit in patients without ASCVD and a consistent increase in bleeding.624,626,627 An updated meta-analysis did not show a reduction in all-cause or CV mortality with aspirin, but did show a lower risk of non-fatal myocardial infarction (RR 0.82) and ischaemic stroke (RR 0.87).628 Conversely, aspirin was associated with a higher risk of major bleeding (RR 1.50), intracranial bleeding (RR 1.32), and major gastrointestinal bleeding (RR 1.52), with no difference in the risk of fatal bleeding (RR 1.09). Bleeding risks were particularly increased in older persons. Other recent meta-analyses found very similar results.629,630 Overall, although aspirin should not be given routinely to patients without established ASCVD, we cannot exclude that in some patients at high or very high CVD risk, the benefits outweigh the risks.632,633 In patients with DM and no evident ASCVD, the ASCEND study reported a 12% risk reduction and a significant increase in major bleeding, but not in fatal or intracranial bleeding.624 A meta-analysis of aspirin for primary prevention in DM found a number needed to treat of 95 to prevent one major adverse ischaemic event in 5 years.625 Hence, as in patients without DM, aspirin may be considered if CVD risk is exceptionally high. Only one in four patients in the ASCEND study were being treated with a proton pump inhibitor. Wider use than this could potentially amplify the benefit of aspirin in primary prevention for patients at higher atherosclerotic risk. In apparently healthy persons <70 years of age with (very) high CVD risk, further studies are needed. Until then, decisions in these high-risk persons should be made on a case-by-case basis, taking both ischaemic risk and bleeding risk into consideration.

4.9.2. Antithrombotic therapy in individuals with established atherosclerotic disease In established atherosclerotic disease, aspirin is associated with significant reductions in serious vascular events, including stroke and coronary events, and a 10% reduction in total mortality.619 These benefits outweigh the bleeding hazards. In patients with previous myocardial infarction, stroke, or LEAD, clopidogrel showed a slight superiority for ischaemic events with respect to aspirin, with a similar safety profile.620 Subgroup analysis suggested a greater benefit of clopidogrel in patients with LEAD. A meta-analysis showed a clinically modest risk reduction with P2Y12 inhibitor monotherapy (number needed to treat: 244), and no effect on all-cause or vascular mortality and major bleeding.621 More guidance on antithrombotic treatment in the specific settings of CAD, cerebrovascular disease, and LEAD, including possible indications for dual pathway inhibition in patients with LEAD, is given in section 6.

4.9.3. Proton pump inhibitors Proton pump inhibitors reduce the risk of gastrointestinal bleeding in patients treated with antiplatelet drugs and may be a useful adjunctive therapy to improve safety.634,635 Proton pump inhibitors that specifically inhibit CYP2C19 (omeprazole or esomeprazole) may reduce the pharmacodynamic response to clopidogrel. Although this interaction has not been shown to affect the risk of ischaemic events, coadministration of omeprazole or esomeprazole with clopidogrel is not recommended.622

4.10 Anti-inflammatory therapy

Acknowledging that the process of atherosclerosis has inflammatory components has led to the investigation of various antiinflammatory therapies in recent years. The first study to examine the effects of reducing inflammation without impacting lipid levels was CANTOS (Canakinumab Antiinflammatory Thrombosis Outcome Study), in which the monoclonal antibody, canakinumab, provided proof-of-concept for anti-inflammatory therapy in high-risk patients.636 This particular drug was, however, not further developed for this indication because of the risk of fatal infections and high costs. Methotrexate was the second antiinflammatory drug studied for this purpose, but was not proven effective in reducing CVD outcomes.637 In 2019, COLCOT (Colchicine Cardiovascular Outcomes Trial) reported a significant reduction (HR 0.77) in CVD outcomes with low-dose colchicine [0.5 mg o.d. (once a day)] in patients with a recent AMI. The more recent LoDoCo2 (second low-dose colchicine) trial reinforced these results in patients with chronic CAD (HR 0.69).85 This study observed a trend towards increased non-CV mortality, which requires further attention. The use of colchicine in daily practice remains to be established based on further clinical study data and experiences in daily practice. Nonetheless, the encouraging results justify consideration of lowdose colchicine in selected, high-risk patients.

Recommendation for anti-inflammatory therapy

Recommendation Classa Levelb

Low-dose colchicine (0.5 mg o.d.) may be considered in secondary prevention of CVD, particularly if other risk factors are insufficiently controlled or if recurrent CVD events occur under optimal therapy.85,86 IIb A

CVD = cardiovascular; o.d. = omni die (once a day). aClass of recommendation. bLevel of evidence. ESC 2021

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In patients with DM at high or very high CVD risk, low-dose aspirin may be considered for primary prevention in the absence of clear contraindications.5,624,625 IIb A Antiplatelet therapy is not recommended in individuals with low/moderate CV risk due to the increased risk of major bleeding.624,626630 III A

ASCVD = atherosclerotic cardiovascular disease; CV = cardiovascular; DM = diabetes mellitus. aClass of recommendation. bLevel of evidence. ESC 2021

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