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• Shared decision-making between patients and healthcare professionals, based on patient-centred care, is paramount in defining the appropriate therapeutic pathway for CCS patients. Patient education is key to improve risk-factor control in the long term. • The relatively high prevalence of ANOCA/INOCA and its associated MACE rate warrants improvement in the diagnosis and treatment of affected patients. • Persistently symptomatic patients with suspected ANOCA/INOCA who do not respond to GDMT should undergo invasive coronary functional testing to determine underlying endotypes. • Characterization of endotypes is important to guide appropriate medical therapy for ANOCA/INOCA patients. • Research on effective methods to support specific healthy lifestyle behaviours, and sustain medication and healthy lifestyle adherence over time, is needed. • More research is needed on improving the implementation of healthpromoting policies and practices in the workplace setting.

8 Gaps in evidence

• It remains unclear if screening for subclinical obstructive CAD in the general population is useful.1106,1210 Further large-scale studies are needed to investigate the prognostic benefit of screening and treating asymptomatic CCS in the general population, preferably involving different geographical regions. Optimal screening options remain to be determined for specific groups at high risk (e.g. asymptomatic individuals with diagnosed diabetes for longer than 10 years). • Most studies assessing diagnostic strategies in individuals with symptoms suspected of CCS were performed in populations with a moderate (>15%–50%) pre-test clinical likelihood of obstructive CAD. Further studies are needed to determine the optimal and most costeffective diagnostic strategy in individuals with a low (>5%–15%) pretest clinical likelihood of obstructive CAD. • The current diagnosis of ANOCA/INOCA and its different endotypes is mainly determined by invasive coronary functional testing.36 Further research is needed to refine and assess non-invasive diagnostic imaging modalities for CMD. Currently available and new non-invasive imaging modalities should be calibrated against invasive testing, allowing the use of their measurements interchangeably. • The role of antithrombotic therapy in CCS patients with ANOCA/ INOCA remains to be established. • Because of how evidence has accrued over time, there is no clear evidence about the existence of first- and second-line antianginal therapy. It is unclear whether long-acting nitrates, ranolazine, nicorandil, ivabradine, trimetazidine, or any of their combinations improve anginal symptoms more than beta-blockers or CCBs. • The optimal type and duration of DAPT is still uncertain in some subsets of patients (e.g. patients with prior revascularization who might benefit from shorter or longer DAPT strategies). • The long-term benefit of beta-blocker therapy in post-MI patients without reduced EF remains to be elucidated. • In view of the reported positive impact of low-dose colchicine in patients with CCS in reducing MI, stroke, and revascularization, future studies should identify whether certain patient subgroups (e.g. those with elevated biomarker levels) might derive even greater clinical benefit from this treatment. • A post hoc analysis of ISCHEMIA detected a graded association between the severity of obstructive CAD assessed by CCTA and all-cause mortality and acute MI during follow-up.317 There is a need for randomized data comparing contemporary medical treatment against early revascularization plus medical therapy in subsets of patients with an increased risk for death or MI as determined by the post hoc analysis. Moreover, because the benefit of an invasive strategy with respect to cardiac mortality was shown in a meta-analysis of chronologically heterogeneous trials, including several conducted more than two decades ago, the impact of early revascularization plus GDMT vs. contemporary GDMT on all-cause and cardiac mortality in patients with CCS should ideally be tested in a well-designed, adequately powered randomized trial. • Some meta-analyses have reported a reduction in cardiac mortality without a reduction in all-cause mortality. There is a need to clarify the impact of revascularization in CCS patients on cardiovascular and non-cardiovascular mortality. • Complete revascularization of multivessel CAD by PCI can be achieved as a single procedure (index PCI) or as staged PCI. In the setting of CCS, the value of staged PCI and the optimal interval between interventions needs to be evaluated. • Whether CABG surgery and PCI are comparable among patients with ischaemic cardiomyopathy and HFrEF in the modern era of HF treatment needs to be evaluated. • Various imaging techniques, such as low-dose DSE, CMR, and PET/ CT, can identify hibernating myocardium with the potential for functional recovery after revascularization.1211 Further randomized trials with contemporary, well-defined modalities and strict adherence to protocol are needed to clarify the clinical benefits (if any) of viability testing. • Residual ischaemia post-PCI, as determined by FFR/iFR, reflects remaining atherosclerotic lesions and/or suboptimal PCI results, but also persistent or worsening microvascular dysfunction. Whether post-PCI FFR/iFR is a ‘modifiable’ risk factor remains to be proved. • Among patients suitable for off-pump CABG with complex multivessel CAD but no LMCAD, the impact of hybrid revascularization on outcomes, including peri-operative complications other than MACE, needs more extensive investigation. Data on the optimal time interval between MIDCAB-LIMA and PCI are lacking. • Whether the decision process based on a multidisciplinary Heart Team leads to better outcomes than standard institutional practice remains to be investigated. • The medical therapy of ANOCA/INOCA is largely empirical. Therefore, prospective randomized clinical trials are needed to determine the efficacy of antianginal treatments in improving symptoms and outcomes for the different endotypes. • Research on effective methods to support healthy lifestyle behaviours, and sustain medication and healthy lifestyle adherence over time, is needed. In addition, more research is needed on improving the implementation of health-promoting policies and practices in the workplace setting. • There is a need for further evidence on the effectiveness of neuromodulation, spinal cord stimulation, therapeutic angiogenesis, and coronary sinus occlusion in patients who suffer from refractory angina, despite guideline-directed medical treatment and revascularization. Downloaded from academic.oup.com/eurheartj/article/45/36/3415/7743115 by guest on 07 October 2026