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atrioventricular conduction disorders,554 and should be used with caution in patients with PAD and chronic obstructive pulmonary disease; (ii) CCBs require caution in patients with heart failure with reduced ejection fraction (HFrEF);526 (iii) ivabradine should not be combined with non-dihydropyridine CCBs (verapamil or diltiazem); and (iv) ranolazine and trimetazidine are reasonable options as part of antianginal combination therapy in patients with low heart rate and/or BP.

4.3 Medical therapy for event prevention

Prevention of coronary ischaemic events is based on lowering the risk of coronary artery occlusion and consequent ACS. Medical eventpreventing therapies include antithrombotic, lipid-lowering, anti-RAAS (renin–angiotensin–aldosterone system), anti-inflammatory, and metabolic-acting agents.

4.3.1 Antithrombotic drugs

The standard antithrombotic treatment of patients with epicardial atherosclerotic CAD is single antiplatelet therapy (SAPT), typically with aspirin. In patients with ACS or post-PCI, standard treatment is dual antiplatelet therapy (DAPT) with aspirin and an oral P2Y12 inhibitor, for a duration of 12 months after ACS (with or without PCI)65 or 6 months after CCS-PCI.1,556 Thus, in ACS or CCS-PCI patients, DAPT is usually replaced by SAPT at some point. Several recent trials have investigated shortened DAPT durations and P2Y12 inhibitor monotherapy post-PCI to reduce the risk of bleeding. On the other hand, in CCS patients with persistently high ischaemic risk and low bleeding risk, extended intensified antithrombotic therapy should be considered. Ultimately, the choice and duration of antithrombotic regimens largely depend on the delicate balance between each individual’s ischaemic and bleeding risks. The mechanisms of action of the most commonly used antithrombotic drugs in CCS patients are depicted in Figure 10.

4.3.1.1 Antiplatelet drugs

For details on antiplatelet drugs, please see Supplementary data, Table S1.

4.3.1.1.1 Aspirin monotherapy. Low-dose aspirin (75–100 mg once

daily) is the traditional drug of choice in patients with CCS, with or without prior MI.557,558 In an individual-patient data meta-analysis of secondary prevention trials (43 000 patient-years), aspirin vs. no aspirin significantly reduced the combined risk of non-fatal MI, non-fatal ischaemic stroke, or death from vascular causes [from 8.2% to 6.7% per year (P < .0001), with relative risk (RR) reductions of 31%, 22%, and 9%, respectively], translating into 15 fewer fatal and non-fatal serious vascular events for every 1000 patients treated for 1 year.558 Aspirin allocation increased major gastrointestinal (GI) and extracranial bleeds, from 0.07% to 0.10% per year (P < .0001), with a non-significant increase in haemorrhagic stroke but reductions of about a fifth in total stroke (from 2.54% to 2.08% per year, P = .002) and in coronary events (from 5.3% to 4.3% per year, P < .0001). Thus, for secondary prevention, the reduction of ischaemic events with aspirin outweighs serious bleeding events.557,558 There is no evidence of different aspirin effects in women and men.558,559 Daily aspirin doses of 75–100 mg seem to be as effective as higher doses for longterm treatments.558–561 4.3.1.1.2. Oral P2Y12 inhibitor monotherapy. 4.3.1.1.2.1. Clopidogrel monotherapy. In addition to the cyclooxygenase-I pathway inhibited by aspirin, the platelet P2Y12 receptor also plays a pivotal role in arterial thrombus formation and is the target for three oral platelet inhibitors: clopidogrel, prasugrel, and ticagrelor. The relative efficacy and safety of clopidogrel compared with aspirin for secondary prevention in CCS patients has been tested in multiple randomized trials that, taken together, have involved over 29 000 patient-years.562,563

In an overall population of 19 185 patients with either previous MI (within 35 days), stroke (within 6 months), or PAD, followed for a mean of 1.9 years, the CAPRIE trial (Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events) demonstrated a small benefit in ischaemic events (RR reduction of 8.7%) with clopidogrel 75 mg/day vs. aspirin 325 mg/day.564 In the recent, open-label, South Korean, non-inferiority HOST-EXAM (Harmonizing Optimal Strategy for Treatment of Coronary Artery Stenosis-EXtended Antiplatelet Monotherapy) trial, clopidogrel was compared with low-dose aspirin in 5530 patients after 6–18 months of uneventful DAPT post-PCI (72% initial ACS, 28% initial CCS).565 Relative to aspirin, clopidogrel reduced the composite of all-cause death, non-fatal MI, readmission attributable to ACS, stroke, and BARC (Bleeding Academic Research Consortium) ≥3 bleeding from 7.7% to 5.7% at the end of the 2-year follow-up; the results were maintained at 5.8 years, in a post hoc, per-protocol, post-trial analysis.566 A very recent individual patient-level meta-analysis examined seven trials involving 24 325 patients (including recent ACS, post-CABG, or initial CCS patients) randomized to either aspirin monotherapy (12 147 patients) or P2Y12 inhibitor monotherapy [clopidogrel in 7545 (62.0%), ticagrelor in 4633 (38.0%)] and followed for 6–36 months.562 P2Y12 inhibitors reduced the combined ischaemic outcome of cardiovascular death, MI, and stroke compared with aspirin (in doses of 100 or 325 mg daily), mainly through reduction of infarction. The risk of major bleeding was similar, whereas GI bleeding and haemorrhagic stroke occurred less frequently with a P2Y12 inhibitor. The treatment effect was consistent across pre-specified subgroups (ACS or CCS) and type of P2Y12 inhibitor.562 The above overall evidence supports clopidogrel monotherapy as an effective and safe alternative to aspirin monotherapy for long-term secondary prevention in patients with CCS.

4.3.1.1.2.2 Ticagrelor monotherapy. Since ticagrelor compared with

clopidogrel is more effective and displays less variable platelet inhibition,567,568 although with greater bleeding potential,569 ticagrelor monotherapy has been compared with aspirin monotherapy for secondary prevention in CCS patients treated with PCI. The RCT GLOBAL LEADERS trial [Ticagrelor plus aspirin for 1 month, followed by ticagrelor monotherapy for 23 months vs. aspirin plus clopidogrel or ticagrelor for 12 months, followed by aspirin monotherapy for 12 months after implantation of a drug-eluting stent (DES): a multicentre, open-label, randomized superiority trial]570 of 15 968 patients (53% with initial CCS) did not show superiority of ticagrelor monotherapy vs. standard of care in terms of survival or new Q-wave MI.570 A pre-specified GLOBAL LEADERS ancillary analysis of independently adjudicated outcomes in 7585 patients reported non-inferiority for ischaemic events and no difference in BARC major bleeding between the two strategies.571 A post hoc landmark analysis of the GLOBAL LEADERS trial, conducted in 11 121 uneventful patients at 1 year (53% CCS from trial onset, 47% transitioning to CCS from Downloaded from academic.oup.com/eurheartj/article/45/36/3415/7743115 by guest on 07 October 2026