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Low CFR is associated with poor prognosis, whereas it is a heterogeneous condition according to the actual coronary flow, such as high resting or low hyperemic coronary flow, which should have different physiological traits and clinical implications. This study aimed to detect and define the sub-phenotypes of vessels with low coronary flow reserve (CFR) epicardial disease by unsupervised machine-learning methods. Hierarchical clustering was applied to 376 vessels from 364 patients with CFR less than the median and fractional flow reserve ≤ 0.8 from a global, multicenter registry. Detailed features of coronary flow physiology and survivals from vessel-oriented composite outcomes (VOCO) were assessed according to the clusters. Clustering defined three distinct physiological subgroups (PS). PS1 (n = 151) were characterized by high resting coronary flow, dominantly left anterior descending artery (LAD) lesions. PS2 (n = 131) were, in contrast, low hyperemic coronary flow, mainly LAD lesions. PS3 (n = 82) mostly consisted of non-LAD lesions with similar flow status to PS1 except for the low hyperemic Pd. Survivals from VOCO were significantly different according to the clusters (p = 0.005) and PS3 had the highest rate of VOCO. In a COX proportional model predicting VOCO, there was a significant interaction between PCI and PSs, suggesting potentially different effects of PCI on outcome between PS1 and PS2. The unsupervised machine-learning approaches provided unique insights into low CFR condition. Among low CFR epicardial lesions, high resting flow with low hyperemic Pd might be related to poor prognosis, and low hyperemic flow in LAD could benefit from elective PCI. CLINICAL TRIAL REGISTRATION INFORMATION: https://clinicaltrials.gov/ct2/show/NCT03690713 , NCT03690713.

Background Sex-specific differences may influence prognosis after deferred revascularization following fractional flow reserve (FFR) measurement. This study sought to investigate the sex differences in long-term prognosis of patients with deferred revascularization following FFR assessment. Methods and Results A total of 879 patients (879 vessels) with deferred revascularization with FFR >0.75 who underwent FFR and coronary flow reserve measurements were enrolled from 3 countries (Korea, Japan, and Spain). Long-term outcomes were assessed in 649 men and 230 women by the patient-oriented composite outcome (POCO, a composite of any death, any myocardial infarction, and any revascularization). We applied inverse-probability weighting based on propensity scores to account for differences at baseline between women and men (age, hyperlipidemia, diabetes mellitus, diameter stenosis, lesion length, multivessel disease, FFR, coronary flow reserve. The median follow-up duration was 1855 days (745-1855 days). Median FFR values were 0.88 (0.83-0.93) in men and 0.89 (0.85-0.94) in women, respectively. The occurrences of POCO were significantly high in men compared with that in women (10.5% versus 4.2%, P =0.007). Kaplan-Meier analysis revealed that women had a significantly lower risk of POCO (χ 2 =7.2, P =0.007). Multivariate COX proportional hazards regression analysis revealed that age, male, diabetes mellitus, diameter stenosis, lesion length, and coronary flow reserve were independent predictors of POCO. After applying IPW, the hazard ratio of males for POCO was 2.07 (95% CI, 1.07-4.04, P =0.032). Conclusions This large multinational study reveals that long-term outcome differs between women and men in favor of women after FFR-guided revascularization deferral. Clinical Trial Registration URL: http://www.ClinicalTrials.gov. Unique identifier: NCT02186093.