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(Supplementary data online, Table S11).302 Over a median 3.3 years of follow-up, the primary efficacy outcome of CV death, MI, or stroke showed a marginal 10% RR reduction by ticagrelor vs. placebo, while both Thrombolysis in Myocardial Infarction (TIMI) major and intracranial bleeding were significantly increased. The pre-specified sub-groups of CABG or previous PCI showed a benefit-risk profile consistent with the entire trial.302,303 The NNT/NNH ratio was 1.5. Thus, an unfavourable benefit-risk profile is associated with adding ticagrelor to ASA in this setting. The COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial enrolled 27 395 patients with stable ASCVD (previous MI, symptomatic CAD, and/or PAD). Low-dose ASA combined with very low-dose rivaroxaban (2.5 mg b.i.d.) was superior to ASA and placebo in preventing MACE (4.1% vs. 5.4%, respectively; HR 0.76; 95% CI, 0.66–0.86; P < 0.001; NNT 77).304 International Society on Thrombosis and Haemostasis-defined major bleeding, but not fatal or intracranial bleeding, was increased (1.9% vs. 3.1%, respectively; HR 1.70; 95% CI, 1.40–2.05; P < 0.001; NNH 83), with an NNT/ NNH ratio of 0.9 (Supplementary data online, Figure S7). The proportional benefit-risk profile of the diabetes sub-group (38% of all patients) was similar to the overall population. Based on these data, adding very low-dose rivaroxaban to low-dose ASA for long-term prevention of serious vascular events should be considered in patients with diabetes and CCS or symptomatic PAD without high bleeding risk.304,305 Data are available up to 47 months of ASA plus very low-dose rivaroxaban exposure; beyond this time, continuation should be determined on an individual basis and with regular evaluation of thrombotic vs. bleeding risks.

5.6.2.2 Acute coronary syndrome

5.6.2.2.1. Peri-procedural management. Peri-procedural management of patients with ACS or undergoing PCI, which may include glycoprotein IIb/IIIa inhibitors, cangrelor, heparins, or bivalirudin, is detailed in the 2018 ESC/European Association for Cardio-Thoracic Surgery (EACTS) Guidelines on myocardial revascularization.299,306–308

5.6.2.2.2 Post-procedural management. In patients with ACS

undergoing PCI, 12 months’ DAPT with low-dose ASA and prasugrel or ticagrelor was superior to DAPT with clopidogrel in the diabetes sub-group of the respective RCTs, with a benefit-risk profile similar to the overall trial populations (Supplementary data online, Tables S12–13).309–312 With the limitations of a subgroup analysis, patients with diabetes on DAPT with low-dose ASA and prasugrel tended to have a more favourable benefit-risk profile.312 The open-label ISAR-REACT 5 (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment) trial randomized 4018 patients with ACS to prasugrel or ticagrelor added to ASA.313 Prasugrel was superior to ticagrelor in reducing MACE without increasing major bleeding, with similar effects in the sub-group of patients with diabetes (n = 892; 22%; Supplementary data online, Table S12).313 Thus, DAPT, i.e. low-dose ASA with prasugrel or ticagrelor are preferred to DAPT with clopidogrel in patients with diabetes and ACS (Supplementary data online, Table S12),309–312 unless the patient is deemed at very high bleeding risk. Of note, patients with T2DM have a reduced generation of the active metabolite of clopidogrel compared with patients without diabetes (Supplementary data online, Section 2.7).323,324 Notably, previous intracranial bleeding contraindicates patients to both prasugrel and ticagrelor. In patients with diabetes and ACS who do not undergo cardiac revascularization, DAPT with ASA (75–100 mg o.d.) and a P2Y12 receptor inhibitor, preferably ticagrelor over clopidogrel, is recommended for 12 months.314,315

5.6.2.2.3 Prolonging DAPT post-ACS. The GLOBAL-LEADERS

(A Clinical Study Comparing Two Forms of Antiplatelet Therapy After Stent Implantation) trial failed to show superior efficacy or safety of 24 months of ticagrelor monotherapy post-ACS vs. the standard 12-month DAPT followed by 12-month low-dose ASA monotherapy in the overall and diabetes (25% of all patients) cohorts.316 The PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin) trial compared prolonged ticagrelor therapy (60 or 90 mg b.i.d.) with placebo added to low-dose ASA in patients with an MI 1–3 years before study entry and additional CV risk factors.317 Reduced-dose ticagrelor (60 mg) decreased MACE compared with placebo (7.77% vs. 9.04%, respectively; HR 0.84; 95% CI, 0.74–0.95; P = 0.004; NNT 79), with no heterogeneity with respect to the diabetes sub-group, whereas it significantly increased TIMI major bleeding (2.3% vs. 1.06%, respectively; HR 2.32; 95% CI, 1.68–3.21; NNH 81), dyspnoea, serious adverse events, and drug discontinuation rates.317 Based on these data, DAPT prolonged beyond 12 months should be considered up to 3 years in patients with diabetes who have tolerated DAPT without major bleeding.63,317,318 The median follow-up across all trials on prolonging full-dose DAPT was 18 months (interquartile range 12–24 months), with a maximum DAPT exposure no longer than 36 months.318 No sufficient safety and efficacy data are available for DAPT with reduced-dose ticagrelor beyond 3 years, especially considering the significant TIMI major bleeding increase of the association (Supplementary data online, Figure S6).317,319

5.6.2.2.4. Shortening or de-escalating DAPT post-ACS in diabetes. No evidence supports shortening or de-escalating DAPT post-ACS specifically in patients with diabetes, since RCTs on shorter DAPT duration followed by ASA or a P2Y12 inhibitor monotherapy are relatively small, often with non-inferiority design for efficacy, relatively low power, and wide noninferiority margins. In addition, these RCTs had primary endpoints combining minor bleeding with traditional efficacy outcomes, efficacy outcomes including not only MACE, and diabetes sub-groups that contain few patients and events, especially on the major hard endpoints (Supplementary data online, Table S13).320,321 Moreover, large, superiority RCTs have failed to show a higher efficacy of routine platelet-function testing in guiding antiplatelet therapy post-PCI.322,322a Of note, the TROPICAL-ACS (Testing Responsiveness to Platelet Inhibition on Chronic Antiplatelet Treatment For Acute Coronary Syndromes) trial ‘deescalating’ P2Y12 inhibition from prasugrel to clopidogrel after 2 weeks of DAPT based on platelet function testing showed an upper HR limit for MACE of 1.93 in the diabetes sub-group (HR 1.17; 95% CI, 0.71–1.93). Moreover, CV death was significantly increased in sub-groups with diabetes vs. without diabetes in the ‘de-escalating’ arm (HR 2.42; 95% CI, 0.61–9.67; Pint = 0.04), thus suggesting harm from de-escalation compared with standard recommended DAPT.321 In addition, patients with diabetes form less of the clopidogrel active metabolite resulting in less platelet inhibition (Supplementary data online, Section 2.7).323,324 Thus, shortening or de-escalating DAPT below 12 months is not recommended in patients with diabetes in the 12 months post-ACS. Current evidence does not support platelet function testing to adjust DAPT. Figure 12 summarizes recommendations in patients with diabetes and ACS or CCS undergoing PCI or CABG.

ESC Guidelines                                                                                                                                                                                          4079

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