Selecting the right patient for CTO-PCI: is ischaemia still the key?

This editorial refers to ‘Implication of myocardial perfusion abnormalities on clinical outcomes in patients treated with percutaneous coronary intervention for chronic total occlusions’, by J.B. Henningsen et al., https://doi.org/10.1093/ehjimp/qyaf137. The management of chronic total occlusion (CTO) remains clinically and technically challenging. With recent advances, CTO percutaneous coronary intervention (CTO-PCI) has achieved procedural success rates exceeding 80–90% when performed by experienced operators.1 However, CTO-PCI carries a reported mortality of 1.3% and coronary perforation rates of ∼4.8%.2 Observational studies suggest that patients with CTO revascularization experience better outcomes than those on optimal medical therapy (OMT), which has prompted increased consideration of CTO-PCI. A recent systematic review of 29 studies with adequate representation of older adults, out of which 28 were observational, demonstrated that attempted CTO-PCI was associated with reductions in all-cause mortality, cardiac death, and major adverse cardiovascular events compared with OMT alone. Additionally, cardiac death and all-cause mortality were lower in successful CTO-PCI vs. failed CTO-PCI.3 However, randomized trials of revascularization in general have not demonstrated a mortality benefit, and findings regarding symptom improvement have been equivocal. Thus, the apparent advantages seen in retrospective studies may be in part due to residual confounding, as patients with successful procedures may differ systematically from those with failed attempts or those not selected for intervention. From a functional standpoint, both the evaluating xience and left ventricular function in PCI on occlusions after STEMI and randomized trial to assess regional left ventricular function after stent implantation in chronic total occlusion trials showed no significant improvement in left ventricular (LV) function with CTO-PCI compared with OMT alone.4 From a prognostic standpoint, the EUROCTO (randomized multi-centre trial to compare revascularization with optimal medical therapy for the treatment of chronic total occlusions) trial demonstrated similar major adverse events with CTO-PCI and OMT at 1 year, however clinically meaningful improvement in health status was observed with CTO-PCI.5 In contrast, the larger DECISION-CTO (Drug-Eluting Stent Implantation vs. Optimal Medical Treatment in Patients With Chronic Total Occlusion) trial showed no superiority of routine CTO-PCI plus OMT over OMT alone in improving symptoms or reducing major cardiovascular outcomes.6 An analysis of patients with CTO from the ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) trial demonstrated that an initial invasive strategy did not reduce mortality, and was associated with more procedural myocardial infarctions (MI), fewer spontaneous MI, and significantly greater improvements in angina and dyspnoea-related quality of life compared with a conservative approach. In an observational comparison of the ISCHEMIA trial, successful CTO revascularization (whether with PCI or CABG) was associated with better quality of life and a higher likelihood of reduced cardiovascular death or MI—although the absolute difference was modest—but not with lower all-cause mortality compared with conservative management.7 However, results of the trials mentioned above should be interpreted in the context of important limitations, including crossover between treatment arms, potential selection and trial entry bias and small sample size. Contemporary guidance has therefore evolved towards a symptom-first paradigm, recommending revascularization primarily to improve health status in patients with refractory angina and functional limitation despite guideline-directed medical therapy, with non-invasive testing used to support decisions The recent clinical consensus statement of the European Association of Percutaneous Cardiovascular Interventions, the European Association of Cardiovascular Imaging, and the ESC Working Group on Cardiovascular Surgery emphasizes the use of non-invasive imaging to define coronary anatomy, quantify inducible ischaemia, evaluate myocardial viability, guide procedural planning, and predict the impact of CTO revascularization on LV remodelling and residual ischaemia.8 Within this framework, myocardial perfusion imaging (MPI) especially with positron emission tomography (PET) holds an promising role in the evaluation of CTO. While MPI confirms ischaemia, several physiologic characteristics of CTO complicate reliance on single photon emission computed tomography (SPECT) MPI alone. Namely, collateral supply, multi-vessel disease, and diffuse microvascular dysfunction can yield balanced or global reductions in relative perfusion, diminishing the sensitivity of SPECT to detect territorial gradients. In contrast, PET offers higher diagnostic accuracy for ischaemia detection and enables quantitative assessment of absolute myocardial blood flow (MBF) and myocardial flow reserve (MFR), thereby revealing diffuse ischaemia that relative images may miss.9–11 The physiologic reversibility of ischaemia after successful recanalization is well documented, quantitative PET studies show significant increases in stress MBF and MFR after CTO-PCI, reflecting relief of collateral burden and improved global perfusion efficiency. These observations, however, have not been paired with robust, prospective links between pre-procedural ischaemia burden and post-PCI hard outcomes in CTO cohorts.12,13 The broader revascularization literature reinforces this nuance. In the nuclear sub study of the COURAGE trial (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation), although not specific to CTO, patients who underwent serial SPECT imaging showed that adding PCI to OMT resulted in greater ischaemia reduction and ischaemia reduction was in turn associated with improved outcomes. However, these findings must be interpreted within the context of the overall trial, which did not demonstrate a difference in hard clinical endpoints between PCI and medical therapy.14 Consequently, while imaging is indispensable for confirming a targetable substrate, current literature shows that baseline ischaemia alone is an insufficient arbiter of whom to re-vascularize. The cohort study by Henningsen et al. addressed an important question of whether baseline ischaemia on MPI influence outcomes after CTO-PCI. The investigators evaluated 319 patients from the Western Danish Heart Registry who underwent nuclear MPI (SPECT or PET) who were treated with CTO-PCI within six months. Moderate-to-severe ischaemia was predefined as ≥10% LV burden, and outcomes included all-cause mortality and MACCE (including cardiovascular death, myocardial infarction, stroke, and hospitalization for heart failure or angina pectoris) at 90 days and 5 years. This study found that baseline moderate to severe ischaemia was not associated with differences in hard outcomes at either time point compared with no moderate-severe ischaemia. However, patients with a greater ischaemic burden had reduced angina hospitalizations at 5 years. Notably, although PET was more frequently used in the moderate-severe ischaemia group, PET-only analysis similarly showed no difference in hard outcomes, likely due to small sample size and under power. These results align with previous evidence demonstrating that CTO-PCI primarily confers primarily symptomatic benefit, and that hard event prognosis does not appear to be driven by baseline ischaemia burden. Collectively, this supports a symptom-first selection paradigm, pending further evidence from randomized CTO trials. Several important limitations warrant consideration. First, the analysis compared outcomes among patients who underwent CTO-PCI according to baseline ischaemia, without an OMT-only comparator group within each ischaemia stratum; thus, it cannot determine whether PCI vs. medical therapy is superior in patients with low vs. high ischaemic burden, and causal inference about revascularization benefit stratified by ischaemia remains limited. Second, imaging heterogeneity introduces potential misclassification: SPECT and PET differ in diagnostic performance, with PET showing higher sensitivity and enabling quantitative MBF/MFR, whereas relative SPECT perfusion can miss collateral-supported or balanced ischaemia; these differences can bias exposure classification. However, since the PET-only analysis yielded similar results, this heterogeneity likely did not influence the overall findings.15 Third, patient reported outcomes were absent: reliance on angina hospitalization under-captures day to day symptom burden and health status gains. Fourth, ischaemia was defined using a global ≥10% LV threshold rather than the extent of ischaemia in the territory corresponding to the CTO vessel, with no data regarding disease in non-CTO-vessels, which may influence ischaemic burden and dilute associations. This could have been overcome by assessment of MBF in the other territories. However, this is only possible with PET imaging at this stage. A vessel-based analysis focusing on the extent of ischaemia in the CTO territory could be more discriminative. Lastly, relying on a single ischaemia cut-off of 10% may be restrictive; exploring alternative thresholds or treating ischaemic burden as a continuous variable may yield additional insights. Despite these limitations, the findings align with the broader body of CTO literature: symptom relief remains the principal demonstrated benefit of CTO-PCI. In sum, convergent evidence from contemporary trials, observational studies, and guideline statements supports a conservative stance: CTO-PCI appears to be an effective tool to relieve angina and improve health status. Non-invasive imaging should confirm that viable, ischaemic myocardium within the CTO territory accounts for the patient’s symptoms to mitigate the procedure risk. Thus, baseline MPI-derived ischaemic burden especially with PET MBF assessment as well as viability imaging is best used as a decision-support tool rather than a binary gate (Figure 1). Patient selection should prioritize refractory or unacceptable level of angina and functional limitation despite guideline-directed therapy (Figure 2). Accordingly, it is essential to prioritize patient reported outcomes by integrating the Seattle Angina Questionnaire, Kansas City Cardiomyopathy Questionnaire, and pragmatic return-to-activity metrics (work status, functional capacity) at baseline and follow-up in future studies. To better strengthen this recommendation, there is a need for CTO-specific randomized trials comparing OMT vs. CTO-PCI directed by PET myocardial perfusion and viability imaging with symptom and quality of life as primary endpoints Future studies should also quantify MFR and peak blood flow within the CTO territory to refine selection and predict the magnitude and durability of clinical benefit. Evidence summary and PET-informed, symptom-driven selection for CTO-PCI. A 70-year-old man with hypertension, hyperlipidaemia, and a family history of coronary artery disease underwent PET MPI for evaluation of chest pain. Baseline PET MPI demonstrated a large, severe perfusion defect in the left anterior descending coronary artery (LAD) territory (42% ischaemia and 12% fixed defect). Gated images showed a drop in LV ejection fraction from 56% at rest to 53% during stress, with akinesis of the hypoperfused segments. Global MFR was markedly reduced (1.1), with regional MFR of 0.62 in the affected territory (Panel A). Coronary angiography revealed a chronic total occlusion of the mid-LAD, 80% stenosis of the second diagonal branch, 100% stenosis of the mid-left circumflex coronary artery, and 40% stenosis of the proximal right coronary artery. Percutaneous coronary intervention with drug-eluting stent placement was performed in the main LAD branch, resulting in 0% residual stenosis in the main vessel and 80% residual stenosis in the side branch (Panel B). Follow-up PET MPI 1 year later demonstrated marked improvement, with resolution of the LAD perfusion defect and only a small (4%) ischaemic defect in the circumflex territory. Wall motion was normal (stress EF 72% and rest EF 69%), with mildly reduced global MFR (1.8) (Panel A). Alaaeddine El Ghazawi (Writing—original draft), Maria Alwan (Writing—review Visualization), and Mouaz Al-Mallah (Conceptualization; Writing—review Supervision) No funding for this editorial. Data is available upon request.