Beyond borderline physiology: determinants of treatment choice and phenotypes of outcome in QFR grey-zone lesions

Introduction

The integration of coronary physiology, notably fractional flow reserve (FFR), has unequivocally demonstrated superior clinical outcomes compared to angiography-guided decision-making for coronary revascularization (1). This paradigm is rooted in evidence that lesions with lower FFR values derive greater benefit from revascularization (2). However, the subsequent landmark DEFER (3,4) and FAME (5-8) trials, while cementing the role of physiology, employed different ischemic thresholds (≤0.75 and ≤0.80, respectively). This created a zone of diagnostic uncertainty—a physiological ‘grey zone’—where the benefit of revascularization is unclear.

The recent advent of angiography-based quantitative flow ratio (QFR) has provided a wire- and hyperemia-free alternative, demonstrating strong diagnostic agreement with FFR (9-12). Furthermore, QFR-guided strategy has been proven superior to angiography guidance alone in improving patient outcomes (13). Despite this advancement, QFR is not exempt from the fundamental challenge of physiological ambiguity. Consequently, the management of lesions in the QFR grey zone (0.75–0.85) remains a persistent clinical dilemma (14).

Therefore, the critical question is no longer whether physiology is useful, but how to personalize management within this ambiguous range. This study addressed this personalized management challenge through a sequential analysis. First, we characterized physician decision-making by identifying the factors that guided treatment selection for a cohort of lesions defined by angiographically intermediate stenosis and a QFR value in the grey zone. We then evaluated the outcomes of these real-world strategies for these lesions. The ultimate goal was to identify phenotypic modifiers of treatment effect, thereby informing a personalized management strategy for this population. We present this article in accordance with the STROBE reporting checklist (available at https://cdt.amegroups.com/article/view/10.21037/cdt-2026-1-0045/rc).

Methods

Study design and population

This retrospective, single-center cohort study was conducted at The First Affiliated Hospital of Xi’an Jiaotong University. The primary objective was to evaluate the association between treatment strategy and clinical outcomes in patients with coronary lesions in the QFR grey zone (0.75–0.85). A total of 297 grey-zone lesions (10 May 2023–30 June 2023) were identified and included in the final analysis. Lesions were stratified based on the actual treatment received into a percutaneous coronary intervention (PCI) group (n=101) or a medication-only therapy group (n=196). The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of The First Affiliated Hospital of Xi’an Jiaotong University (No. LLSBPJ-2024-233) and individual consent for this retrospective analysis was waived.

Data collection, QFR, and SYNTAX score analysis

Baseline clinical characteristics were extracted from electronic medical records. QFR analysis was performed using the AngioPlus mQFR system (Shanghai Pulse Medical, Shanghai, China). The analysis was conducted retrospectively by an experienced physician, blinded to patient outcomes and treatment allocation, Patients were eligible if they had an intermediate coronary stenosis (30%–70% diameter stenosis) in a major epicardial vessel that met the standard AngioPlus criteria for adequate monoplane QFR (mQFR) analysis (15,16), which requires optimal contrast filling and minimal vessel overlap in a single angiographic projection. All coronary angiograms were performed electively for the diagnostic evaluation of stable ischemic symptoms or suspected coronary artery disease. Patients presenting with acute coronary syndromes (ACS), including unstable angina, non-ST-elevation myocardial infarction, or ST-elevation myocardial infarction, were excluded to ensure QFR assessment reflected stable physiological conditions. Additional key exclusion criteria comprised insufficient angiographic quality for mQFR, stented target vessels, chronic total occlusions, ostial left main or ostial right coronary artery lesions, and prior coronary artery bypass grafting (CABG) involving the target vessel. Furthermore, patients with severe valvular heart disease, left ventricular hypertrophy (LVH), or abnormal left ventricular global longitudinal strain (LVGLS) were excluded to avoid confounding of QFR interpretation by microvascular dysfunction.

Study endpoint

The primary endpoint was target vessel failure (TVF) at clinical follow-up. TVF was defined as a composite of cardiac death, target vessel myocardial infarction, or ischemia-driven target vessel revascularization. The mean follow-up duration for the cohort was 526 days. To minimize ascertainment bias, researchers blinded to QFR results and treatment allocations adjudicated all endpoint events based on source documentation from hospital records and structured telephone interviews.

Statistical analysis

Baseline characteristics were compared between the PCI and medication groups at both the patient and lesion levels to identify factors associated with treatment selection, continuous variables are presented as mean ± standard deviation and were compared using Student’s t-test or Mann-Whitney U test. Categorical variables are presented as numbers (percentages) and were compared using Chi-square or Fisher’s exact test.

The association between treatment strategy and TVF was assessed using Kaplan-Meier curves with the log-rank test. To adjust for potential confounders, a multivariable Cox proportional hazards model was constructed. Due to high multicollinearity among independent variables, predictor selection was informed by principal component analysis and clinical relevance. To avoid overfitting given the low event rate (n=10), we constructed a parsimonious multivariable Cox proportional hazards model including only clinically relevant predictors. The final model included age, sex, BMI, hypertension, hypercholesterolemia, diabetes, HbA1c, left ventricular ejection fraction (LVEF) >45%, proBNP, eGFR, flow velocity, minimum lumen diameter (MLD), diameter stenosis (DS%), lesion length, SYNTAX I score, and treatment method. Medication data and microcirculatory resistance (MR) were collected but not included in the primary model, as both showed non-significance in exploratory analyses. Furthermore, medications were prescribed based on treatment selection and underlying clinical conditions (introducing confounding by indication), and MR demonstrated significant multicollinearity with QFR. Including these additional variables would also risk model overfitting. Exploratory models including medications and MR are provided in the Tables S1,S2.

A pre-specified sub-analysis was conducted to explore heterogeneity within the QFR grey zone and to investigate whether the association between clinical predictors and TVF was modified by the QFR value. The grey zone was divided into two sub-ranges (0.75–0.80 and 0.81–0.85). From the primary multivariable Cox model, (LVEF ≤45%) was identified as an independent predictor of TVF. We therefore focused subsequent analysis on this variable, evaluating its association with TVF across the QFR sub-ranges and within each treatment group using Chi-square, Fisher’s exact, and Mantel-Haenszel tests to identify specific subgroups at highest risk.

A two-sided P value <0.05 was considered statistically significant. All analyses were performed using IBM SPSS Statistics for Windows, Version 27.0.

Results

Study population and baseline characteristics

The final analysis included 297 grey-zone lesions (QFR 0.75–0.85) from 297 patients. Of these, 101 lesions (34.0%) were treated with PCI and 196 (66.0%) were managed with medication-only therapy.

Baseline characteristics are summarized in (Table 1). Patients selected for medical therapy had higher HbA1c levels (6.78%±1.44% vs. 6.39%±1.15%, P=0.006) and elevated proBNP (890.4±2,627.2 vs. 573.4±1,688.7 pg/mL, P=0.020).

Conversely, Lesions treated with PCI exhibited smaller minimum lumen diameter (MLD 1.52±0.39 vs. 1.73±0.48 mm, P<0.001), higher diameter stenosis (DS% 51.29%±5.76% vs. 45.07%±6.19%, P<0.001), and greater area stenosis (AS% 75.92%±5.71% vs. 69.44%±6.78%, P<0.001). The PCI group also had lower QFR values (0.80±0.03 vs. 0.81±0.02, P=0.008) and lower flow velocity (14.89±4.99 vs. 16.59±6.08 cm/s, P=0.03). A trend toward higher resting microvascular resistance was observed in the PCI group (resting MR 5.22±1.95 vs. 4.77±1.68, P=0.055). Medically managed lesions more frequently had length >20 mm (74.5% vs. 63.4%, P=0.046).

Clinical outcomes: PCI vs. medical therapy

During a mean follow-up of 526 days, the primary endpoint of TVF occurred in 10 lesions (3.4%): 7 events (3.6%) in the medication group and 3 events (3.0%) in the PCI group. Kaplan-Meier analysis demonstrated no significant difference in TVF rates between the PCI and medication groups (log-rank P=0.76) (Figure 1).

Figure 1 Kaplan-Meier curves for TVF by treatment strategy. PCI, percutaneous coronary intervention; TVF, target vessel failure.

In the multivariable Cox proportional hazards model (Table 2), which adjusted for clinical, laboratory, and angiographic confounders, treatment strategy (PCI vs. medication) was not associated with TVF risk (HR 0.945, 95% CI: 0.187–4.787, P=0.95). The only independent predictors of TVF were higher HbA1c (HR 2.038, 95% CI: 1.103–3.763, P=0.02) and LVEF >45% (HR 0.055, 95% CI: 0.006–0.548, P=0.01) (Figure 2).

Figure 2 Hazard function stratification for TVF. (A) Hazard function for TVF by treatment group (PCI vs. medication). (B) Hazard function for TVF by LVEF strata (≤45% vs. >45%). LVEF, left ventricular ejection fraction; PCI, percutaneous coronary intervention; TVF, target vessel failure.

Interaction between LVEF and QFR on TVF risk

Given that treatment strategy was not a significant determinant of outcome and LVEF showed a strong association with TVF in the primary model, we investigated LVEF further. A significant interaction was found between LVEF and QFR value (P for interaction =0.040).

The QFR grey zone was divided into lower (0.75–0.80) and upper (0.81–0.85) sub-ranges, and the association between LVEF and TVF was analyzed within each treatment and QFR stratum (Table 3). In the PCI-treated group, no significant association between impaired LVEF and TVF was observed in either QFR sub-range (QFR ≤0.80: P>0.99; QFR >0.80: P>0.99). In the medication-treated group, impaired LVEF was significantly associated with TVF in the lower QFR sub-range (QFR ≤0.80: P=0.04) but not in the upper sub-range (QFR >0.80: P=0.39). The Mantel-Haenszel test, controlling for QFR sub-range, demonstrated a significant overall association between impaired LVEF and TVF among medically managed patients (OR: 0.161; 95% CI: 0.034–0.774; P=0.02).

To visualize these observations, we performed Kaplan-Meier cumulative hazard analysis in the medication group, stratified by LVEF and QFR sub-range. This analysis demonstrated significant differences in TVF risk among groups (log-rank P<0.001), with the highest cumulative hazard observed in patients with LVEF ≤45% and QFR ≤0.80 (Figure 3).

Figure 3 Total Kaplan-Meier target vessel failure: the total TVF curve showed that the incidence of TVF is different among four groups (P<0.001). LVEF, left ventricular ejection fraction; QFR, quantitative flow ratio; TVF, target vessel failure.

Discussion

This analysis of patients with intermediate coronary lesions (QFR 0.75–0.85) yields three principal findings. First, real-world treatment selection was strategic: PCI was preferred for anatomically severe lesions, while medical therapy was chosen for patients with metabolic or clinical risk factors. Second, despite these baseline differences, overall TVF rates did not differ between treatment strategies. Third, patient-specific factors proved to be the primary determinants of outcome. Impaired LVEF (≤45%) and elevated HbA1c independently predicted TVF, with the risk from LVEF impairment concentrated in medically managed patients with lower-range QFR (≤0.80). This suggests a high-risk phenotype that may derive particular benefit from revascularization.

Determinants of treatment strategy

This study delineates key patient and lesion characteristics that guided clinician judgment in the management of angiographically intermediate coronary lesions. The decision to perform PCI was predominantly driven by the anatomic severity of the stenosis, as clearly evidenced by the significantly smaller MLD, higher DS%, and greater AS% in the PCI group. In this retrospective analysis, these objective morphological metrics were powerfully complemented by core-lab physiological data, which confirmed that the lesions selected for PCI were, in fact, more likely to impede coronary flow, as shown by their lower QFR and flow velocity.

Conversely, patients allocated to medical therapy presented with features suggesting a phenotype less likely to benefit from focal revascularization. This included a worse glycemic control (higher HbA1c), which is associated with more complex and diffuse coronary disease (17-20), and elevated proBNP, indicative of overall poorer cardiac function. Anatomically, the greater prevalence of long lesions (>20 mm) in the medical group—a known marker of procedural complexity—further reinforces the clinical tendency to defer intervention in this setting. In summary, the treatment strategy in this grey-zone cohort appears to balance a preference for PCI in lesions with focal, high-grade severity against a strategy of optimal medical therapy for patients with signs of diffuse atherosclerosis and higher clinical complexity.

Determinants of TVF risk in the QFR grey zone

Our study challenges the management of coronary lesions in the QFR grey zone by demonstrating that patient-specific factors, not treatment strategy alone, are the primary determinants of clinical outcome. While overall rates of TVF were equivalent between PCI and medical therapy, a closer look shows that this average result hides major differences in risk for different types of patients. The principal finding of this study is that LVEF and glycemic control (HbA1c) delineate distinct risk phenotypes. Specifically, impaired LVEF (≤45%) identified patients at significantly heightened risk for TVF when managed medically, an effect that was specially driven by lesions in the lower end of the grey zone (QFR 0.75–0.80). while, elevated HbA1c was a consistent predictor of TVF risk in the medication group across the entire grey-zone spectrum.

Refining our understanding of the physiological grey zone

The management of coronary lesions falling within the physiological “grey zone” remains a subject of ongoing debate, as highlighted by the landmark FFR trials of DEFER (3,4) and FAME (5-8). While these studies established the superiority of physiology-guided revascularization over angiographic guidance alone, they also revealed variability in clinical outcomes for intermediate lesions. Some reports indicated no significant benefit from revascularization compared to medical therapy alone (21-23), while others associated deferral with higher rates of major adverse cardiac events (MACE) and angina (24) as well as higher risk of TVF (25). This clinical ambiguity has spurred the interest in adjunctive risk stratification in the grey zone, including further ischemia testing with coronary flow reserve (CFR) (26), or by analyzing lesion-specific characteristics (27), as well as biomarkers such as high-sensitivity C-reactive protein (hs-CRP) (28).

Our findings with the QFR corroborate the complex nature of physiological grey-zone lesions, wherein a uniform approach—whether toward revascularization or medical management—appears insufficient. Instead, our results underscore the importance of individualized patient assessment. In particular, we identified LVEF and glycemic control (HbA1c) as significant determinants of TVF, suggesting their potential utility in refining prognostic evaluation and personalizing treatment strategies in this challenging patient subset.

High-risk phenotypes in the grey zone: impaired left ventricular function

The prognostic significance of LVEF in cardiovascular disease is well-established. In heart failure populations, an LVEF ≤45% serves as a critical threshold for predicting increased mortality and cardiovascular risk (29,30). Similarly, in the context of coronary artery disease, impaired LVEF is an independent predictor of adverse events, including rehospitalization for acute MI and heart failure following angiography (31).

Evidence suggests that revascularization may modify this risk. In patients with severe ischemic left ventricular systolic dysfunction, PCI has been associated with a reduction in unplanned revascularizations (32). Furthermore, improvements in LVEF following PCI are linked to better long-term outcomes, including reduced mortality and sudden cardiac arrest risk (33-36), with benefits predominantly observed in patients with reduced—as opposed to preserved—baseline LVEF (35).

Our findings are consistent with this established body of evidence. We confirmed that impaired LVEF (≤45%) was a powerful predictor of TVF. Crucially, this risk was almost entirely borne by patients managed medically. The markedly attenuated risk observed in PCI-treated patients with similarly impaired LVEF suggests that revascularization may confer a protective effect, potentially by alleviating ischemia, thereby attenuating the risk associated with ventricular dysfunction.

High-risk phenotypes in the grey zone: poor glycemic control

The management of coronary artery disease in patients with diabetes presents unique challenges, characterized by a more diffuse and calcified atherosclerotic burden even under controlled lipid levels (17-20). While physiological guidance—whether by FFR or QFR—has consistently proven superior to angiography-based decision-making in this population (37,38), a critical question persists: are the outcomes of physiology-guided management equivalent to those in non-diabetic patients?

Evidence remains conflicted. Despite physiological guidance, patients with diabetes exhibit higher rates of MACE (39), with studies of deferred lesions noting increased risks of target lesion failure (TLF) (40), death, target vessel MI (41), and MACE (42). This residual risk may be attributed to an anatomical-functional discordance. As demonstrated by Geng et al. [2023] (43), patients with poor glycemic control and intermediate lesions often exhibit high-risk intravascular ultrasound (IVUS) features despite non-ischemic QFR values, suggesting that physiology alone may not fully capture the underlying plaque vulnerability in diabetes.

This study demonstrates that in patients with diabetes, the inherent diagnostic uncertainty of a borderline QFR measurement cannot be overlooked. Our findings indicate that glycemic status must be incorporated into the clinical decision-making process, as elevated HbA1c identified a subgroup with a significantly higher overall risk for TVF. Therefore, the optimal management strategy for these complex patients should be guided by an integrated assessment that carefully weighs the lesion’s ambiguous physiology and anatomical complexity against the patient’s systemic metabolic risk profile. A borderline QFR result in the context of poor glycemic control may signify a higher-risk state that warrants more intensive management, which could include enhanced medical therapy, closer follow-up, or potentially a lower threshold for considering revascularization based on complementary imaging or clinical context.

Limitations

This study has several limitations. First, as a post-hoc analysis of a prospective registry, the non-randomized treatment allocation introduces the potential for selection bias, despite multivariable adjustment. Second, the generalizability of our findings may be influenced by the single-center design. Third, the physiological assessment of lesion severity using QFR, while robust, assumes normal hyperemic flow. As highlighted by recent work on coronary microvascular dysfunction (CMD) (44), this assumption may not hold in clinical conditions such as CMD or LVH, where blunted hyperemic responses could potentially skew QFR values. Fourth, the overall rate of TVF was low, which limits the statistical power to detect smaller treatment effects. Finally, despite our efforts, residual confounding from unmeasured factors cannot be entirely excluded. Prospective validation in larger, multicenter registries is warranted to confirm the prognostic role of LVEF and glycemic control, and to assess the real-world impact of integrating these factors into clinical decision-making for grey-zone lesions.

Conclusions

In this cohort of patients with QFR grey-zone lesions, treatment selection balanced anatomic severity against clinical complexity. Although overall outcomes were similar between strategies, impaired LVEF (≤45%) identified a high-risk phenotype for whom medical therapy was associated with worse outcomes. Additionally, poor glycemic control independently predicted TVF across the entire cohort. These findings suggest that a more personalized approach—potentially including a lower threshold for revascularization in patients with reduced LVEF and intensified risk factor management in those with poor glycemic control—warrants further investigation.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://cdt.amegroups.com/article/view/10.21037/cdt-2026-1-0045/rc

Data Sharing Statement: Available at https://cdt.amegroups.com/article/view/10.21037/cdt-2026-1-0045/dss

Peer Review File: Available at https://cdt.amegroups.com/article/view/10.21037/cdt-2026-1-0045/prf

Funding: This work was supported by the National Natural Science Foundation of China under grant (No. 82474212).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cdt.amegroups.com/article/view/10.21037/cdt-2026-1-0045/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of The First Affiliated Hospital of Xi’an Jiaotong University (No. LLSBPJ-2024-233) and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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