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The above trial data570–573 and meta-analytical data562,563,574 suggest that ticagrelor monotherapy may be an option for selected CCS or stabilized post-ACS patients treated with PCI. However, the overall evidence is weaker than for other recommended antithrombotic strategies. Moreover, the optimal timing and duration (longest tested duration 23 months) are unclear. Only the 90 mg b.i.d. regimen has been tested as monotherapy.573,575 Data on prasugrel monotherapy for CCS patients are limited to a single-armed, open-label study with 3 months of follow-up.576 In summary, for long-term secondary prevention in CCS patients without an indication for oral anticoagulant (OAC), aspirin or, as an alternative, clopidogrel monotherapy are generally recommended. In selected patients at high ischaemic risk without high bleeding risk (HBR), ticagrelor monotherapy may be considered [at the time of writing not contemplated by the European Medicines Agency (EMA) (https:// www.ema.europa.eu/en/medicines/human/EPAR/brilique)] with a lower level of evidence than for aspirin or clopidogrel (Figure 11). Details on the pharmacology of antiplatelet drugs567,577–582 and on the randomized evidence (including trial limitations) can be found in the Supplementary data, Table S1 and in the evidence tables.

4.3.1.1.3 Dual antiplatelet therapy post-percutaneous coronary

intervention. After PCI for CCS, DAPT consisting of aspirin and clopidogrel is recommended to reduce the risk of stent thrombosis and MI compared with aspirin alone.556 With few exceptions, there is no reason to replace clopidogrel with ticagrelor, based on the ALPHEUS (Assessment of Loading with the P2Y12 Inhibitor Ticagrelor or Clopidogrel to Halt Ischemic Events in Patients Undergoing Elective Coronary Stenting) trial results demonstrating, in 1883 patients followed for 30 days, that ticagrelor did not significantly reduce PCI-related MI or major myocardial injury, while minor bleeding was significantly increased compared with clopidogrel.583 In the THEMIS trial (The Effect of Ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study) of 19 220 CCS patients aged ≥50 years, with type 2 DM and no previous MI or stroke (58% with prior PCI), ticagrelor plus low-dose aspirin marginally reduced ischaemic events compared with placebo plus aspirin at a median follow-up of 40 months, but increased major bleeding, including intracranial haemorrhage.584 A default DAPT duration of 6 months is recommended for CCS patients undergoing PCI.556 However, multiple RCTs have investigated shorter DAPT durations (1 or 3 months) to decrease the risk of bleeding.570,573,585–588 The combined evidence indeed shows a decrease in—mostly minor—bleeding, without an increase in ischaemic events, indicating that a shorter duration of DAPT of 1–3 months post-PCI may benefit CCS patients who are not at high ischaemic risk or who are at HBR. This concept was tested in the MASTER-DAPT trial (Management of High Bleeding Risk Patients Post Bioresorbable Polymer Coated Stent Implantation with an Abbreviated versus Standard DAPT Regimen), randomizing 4579 PCI patients (∼50% CCS) with HBR, after 1-month uneventful DAPT, to immediate DAPT discontinuation or to DAPT continuation for at least 2 additional months.587 After 335 days, the trial demonstrated that discontinuation was non-inferior for ischaemic events compared with standard duration of DAPT, but major and clinically relevant non-major bleeding was reduced.587 A meta-analysis, including 11 RCTs and 9006 patients (42% CCS) at HBR [defined by a PREdicting bleeding Complications In patients undergoing Stent implantation and subsEquent Dual AntiPlatelet Therapy (PRECISE-DAPT) score of >25 or by Academic Research Consortium for High Bleeding Risk (ARC-HBR) criteria, listed in Supplementary data, Table S2]589–591 showed at 12 months of follow-up that an abbreviated DAPT of 1–3 months reduced both major bleeding and ischaemic events, as well as cardiovascular mortality, compared with standard DAPT, irrespective of CCS or ACS presentation.591

The overall data indicate that, in CCS patients with HBR, DAPT discontinuation 1–3 months after PCI is recommended, while in patients without HBR, DAPT duration may be reduced only in the absence of high ischaemic risk (Figure 11). For patients at high ischaemic risk without HBR, see below.

4.3.1.1.4 Extended intensified antithrombotic therapy. In patients at

high ischaemic risk without HBR, there are three options for intensifying antithrombotic therapy to prevent ischaemic events, albeit at the cost of increased bleeding: (i) continue DAPT, consisting of aspirin and clopidogrel or of aspirin and prasugrel after PCI, based on the results of the DAPT Study;592 (ii) add ticagrelor to aspirin in post-MI patients, based on the PEGASUS-TIMI (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin - Thrombolysis In Myocardial Infarction) 54 trial;593 or (iii) add very low-dose rivaroxaban to aspirin in CCS patients, based on the COMPASS trial (Cardiovascular Outcomes for People Using Anticoagulant Strategies).594 The randomized DAPT Study demonstrated, in patients at 1-year post-PCI, that an additional 18 months of DAPT reduced ischaemic events compared with aspirin alone, but moderate and severe GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries) or BARC bleeding rates were higher, and allcause death tended to be increased.592 Of note, in the DAPT Study, firstgeneration DES were used with an increased risk of stent thrombosis. The PEGASUS-TIMI 54 trial showed that in aspirin-treated patients with a history of MI 1–3 years previously and at least one high-risk characteristic (i.e. aged >65 years, DM, second MI, multivessel CAD, or CKD), ticagrelor (90 or 60 mg b.i.d.) vs. placebo reduced ischaemic events at 3 years, while it increased TIMI (Thrombolysis In Myocardial Infarction) major, but not fatal, bleeding.593 The 60 mg dose was safer and better tolerated than the 90 mg dose584,593 and therefore approved. The subgroups of patients with (compared with those without) DM, multivessel CAD, and PAD benefited more from ticagrelor.595–597 The COMPASS trial demonstrated that the combination of aspirin plus rivaroxaban 2.5 mg b.i.d., but not rivaroxaban 5.0 mg b.i.d. monotherapy, reduced ischaemic events, but increased modified-ISTH (International Society on Thrombosis and Haemostasis) major bleeding, compared with aspirin alone in patients with stable atherosclerotic disease (mostly CAD, with additional risk conditions if younger than 65 years).594 There was no significant difference in intracranial or fatal bleeding between the two treatment arms, and death rates were lower in the aspirin plus rivaroxaban 2.5 mg b.i.d. group. Subgroups of patients with (compared with those without) DM, PAD, mild CKD, and active smoking habit benefited more from aspirin plus rivaroxaban.594,598 Patient eligibility for extended intensified antithrombotic therapy must be defined taking into account individual patient characteristics (see Supplementary data, Table S2), as well as study inclusion and exclusion criteria. The different options are described in Table 8. In summary, in high ischaemic risk CCS patients without HBR, either aspirin plus ticagrelor 60 mg b.i.d. or aspirin plus rivaroxaban 2.5 mg b.i.d. should be considered, based on patient characteristics (Figure 11). DAPT prolongation with clopidogrel or prasugrel may also be an option, although the evidence for this choice suffers limitations. In patients with extended intensified antithrombotic therapy, reevaluation of bleeding and ischaemic risk at regular intervals is essential. Randomized evidence beyond study follow-up times is unavailable. Downloaded from academic.oup.com/eurheartj/article/45/36/3415/7743115 by guest on 07 October 2026