Diagnostic Accuracy of Quantitative Coronary Analysis as Compared with Instantaneous Wave-Free Ratio in Intermediate Coronary Lesions: A Prospective Vessel-Level Study

Abstract

Background

Instantaneous wave-free ratio (IFR) represents a new vasodilator-free innovative approach which is considered as a gold standard for functional assessment of the hemodynamic significance of intermediate coronary stenoses. Although relatively safe, iFR is still an invasive procedure that has its potential hazards, complications and cost. Two-dimensional quantitative coronary analysis (2D-QCA) is a non-invasive technique that has emerged robustly as an excellent and attractive tool for delineating coronary anatomy.

Aims

To assess the ability of two-dimensional quantitative coronary analysis (2D-QCA) to guide decision-making for quantification of severity of intermediate coronary stenoses (40–80% diameter stenosis) in each of the three main coronary vessels, by evaluating its accuracy in predicting true instantaneous wave-free ratio (iFR) results.

Methods and results

2D-QCA followed by iFR were performed for intermediate coronary lesions (40–80% diameter stenosis by visual assessment) discovered during coronary angiography. 2D-QCA was used to measure MLA, MLD and lesion length. This was followed by iFR measurement for the same lesion. 2D-QCA was then compared to the iFR measurements in order to assess its accuracy in prediction of true iFR result. A total of 277 intermediate lesions (155 LAD, 67 LCX, 55 RCA) in 209 vessels from 166 patients were analyzed. Males comprised ~68% of cases; mean ages were 53.3 ± 8.2 (LAD), 55.7 ± 8.9 (LCX), and 56.0 ± 8.8 years (RCA). Disagreement between modalities occurred mostly in LAD (24.5%), followed by RCA (21.8%) and LCX (14.9%). Per-vessel QCA accuracy (AUC) for predicting iFR was highest in LCX (78.5%), then RCA (72.2%), and lowest in LAD (66.6%) (all p < 0.005). Optimal QCA stenosis area cutoffs were 50.5% (LCX), 52.5% (RCA), and 53.5% (LAD), with sensitivities of 72.0%, 62.1%, and 63.2%, and specificities of 69.0%, 65.4%, and 65.8%, respectively.

Conclusion

2D-QCA can be a practical tool that bears the potential of improving angiography-based assessment of intermediate lesions regarding its prediction for functional significance without any additional costs, especially when invasive functional assessment methods are not available or contraindicated. Although, this would minimize the burden and the time of invasive procedure, 2D-QCA cannot totally replace invasive functional assessment (iFR, FFR) of intermediate coronary stenoses especially in LAD intermediate lesions.

1. Introduction

1.1. Background

Coronary artery disease (CAD) remains the leading cause of mortality worldwide. Coronary angiography is the reference standard for the anatomical assessment of coronary stenosis; however, visual estimation is inherently subjective and subjected to significant inter-observer variability [1], Myocardial ischemia is a major determinant of adverse cardiovascular events, and revascularization of ischemia-producing lesions improves prognosis and functional capacity [2]. Conversely, multiple trials have demonstrated no prognostic benefit from percutaneous coronary intervention (PCI) in hemodynamically insignificant stenosis [3,4].

1.2. Current evidence

Long-term outcome studies have shown that fractional flow reserve (FFR), a pressure-derived physiological index, improves patients outcomes and reduces healthcare costs when used to guide PCI in intermediate-grade stenosis [4]. Consequently, European Society of Cardiology (ESC) and European Association for Cardio-Thoracic Surgery (EACTS) guidelines recommend FFR as the standard for functional lesion assessment in 40–90% stenosis.

More recently, the instantaneous wave-free ratio (iFR) has emerged as a vasodilator-free alternative to FFR, avoiding the need for pharmacological hyperemia while providing equivalent diagnostic and clinical outcomes. Randomized controlled trials have demonstrated the non-inferiority of iFR compared with FFR for revascularization guidance [5–7].

On the other hand, Quantitative coronary angiography (QCA) offers an anatomical, image-based measurement of stenosis severity through digital caliper-based diameter quantification after calibration with the guiding catheter. It was first introduced by Brown et al. using hand-traced Cin angiograms and computer-assisted correction [8]. But recent advances in digital imaging, automated edge-detection, and micro processing reduced analysis time, enhanced flexibility, and lowered inter-operator variability [9]. Modern QCA systems achieve high-resolution imaging and use automated algorithms to refine vessel borders and derive accurate coronary dimensions [10,11].

1.3. Knowledge gap

The 2018 ESC revascularization guidelines highlight the absence of randomized trials directly comparing iFR-guided revascularization with angiography-guided revascularization or optimal medical therapy [12]. Furthermore, limited data exist comparing anatomical QCA-based decision-making with iFR-based physiological assessment at the vessel level.

In recent years, several angiography-derived physiological techniques, including quantitative flow ratio (QFR), vessel fractional flow reserve (vFFR), and FFRangio, have emerged as promising alternatives for functional lesion assessment. These technologies combine angiographic imaging with computational modeling to estimate physiological significance without pressure-wire instrumentation. However, their availability remains limited in many healthcare systems because of software requirements, technical expertise, and additional costs. Consequently, conventional 2D-QCA continues to represent the most widely accessible quantitative angiographic technique worldwide. Understanding its current diagnostic value remains clinically relevant, particularly in resource-constrained settings [13–16].

1.4. Study rationale and objective

The present study aims to assess the ability of two-dimensional quantitative coronary analysis (2D-QCA) to guide decision-making for quantification of severity of intermediate coronary stenoses (40–80% diameter stenosis) in each of the three main coronary vessels, by evaluating its accuracy in predicting true instantaneous wave-free ratio (iFR) results for proper functional assessment.

2. Patients and methods

This prospective analytical cohort study was conducted at the National Heart Institute and El Fayoum University Hospital, Egypt, between December 2022 and August 2024. Both centers are high-volume tertiary cardiac institutions, ensuring a representative cohort of patients evaluated for suspected coronary artery disease. Ethical approval for the study protocol was obtained in 2019, prior to study initiation. Patients recruitment and data collection were performed from December 2022 to August 2024, and written informed consent was obtained from all participants. A flow diagram summarizing patients screening, exclusions, lesion allocation, and follow-up is presented in Fig. 1.

Fig. 1.

Flowchart of study design and lesion enrollment.

This flowchart summarizes patient screening, eligibility assessment, lesion distribution, QCA analysis, operator-intended management, physiological assessment using iFR, final treatment decisions, and 6-month clinical follow-up. It outlines the full pathway from initial angiography to final management based on iFR ≤0.89.

After exclusion of 17 patients from 183 eligible patients, we enrolled 166 consecutive adult patients (≥18 years) undergoing diagnostic coronary angiography who demonstrated intermediate coronary stenosis on visual assessment, defined as 40–80% diameter stenosis in any major epicardial vessel. Patients were excluded if they had significant left main disease, chronic total occlusion, severe calcification or tortuosity precluding accurate QCA analysis, culprit lesions of acute coronary syndrome or STEMI, hemodynamic instability, cardiogenic shock, intra-aortic balloon pump use, advanced hepatic or pulmonary disease, malignancy with life expectancy less than two years, comorbidities limiting survival to less than two years, pregnancy, or refusal to provide informed consent.

All participants underwent standardized baseline clinical evaluation, including detailed cardiovascular risk assessment, 12-lead electrocardiography, transthoracic echocardiography, and routine laboratory investigations. Coronary angiography was performed using standard techniques via radial or femoral access with diagnostic catheters, and angiographic projections were optimized to minimize vessel overlap and foreshortening.

All intermediate lesions were subsequently analyzed offline using PaxeraView PRO software with automated calibration. Measurements were obtained in the end-diastolic frame to minimize motion artifact, and the least foreshortened view was selected for each lesion.

Quantitative coronary angiography (QCA) measurements included minimal lumen diameter, minimal lumen area, lesion length, and percent diameter stenosis. Lesion number, vessel territory, and procedure duration were also recorded. Lesions were categorized according to vessel territory (LAD, LCX, RCA), stenosis severity (40–60% vs 61–80%), and anatomical segment (proximal, mid, distal, side branch). A more granular per-segment analysis was performed but will be reported separately in a future publication due to the larger sample size required for accurate interpretation.

Before physiological assessment, operators documented their intended management strategy—PCI or medical therapy—based solely on angiographic appearance and QCA measurements. Instantaneous wave-free ratio (iFR) was then measured using Volcano software. A pressure guidewire was advanced distal to the lesion after equalization, and iFR was recorded during the diastolic wave-free period without pharmacologic hyperemia. Three stable measurements were averaged for accuracy.

Lesions were classified as physiologically significant if iFR ≤0.89, prompting PCI, and non-significant if iFR >0.89, prompting medical therapy. In accordance with contemporary guidelines and ethical standards, iFR served as the decisive modality for revascularization in all cases.

All collected data were coded, revised, and entered into Microsoft Excel 2013, then analyzed using SPSS version 22 (IBM Corp., Armonk, NY). Qualitative variables were expressed as frequencies and percentages, whereas quantitative variables were summarized as mean ± standard deviation for normally distributed data.

Because the primary objective was to evaluate the ability of QCA stenosis percentage to classify lesions as physiologically significant (iFR ≤0.89) or nonsignificant (iFR >0.89), diagnostic accuracy rather than correlation analysis was performed. Receiver operating characteristic (ROC) curve analysis was conducted separately for the LAD, LCX, and RCA. Diagnostic performance was summarized by the area under the curve (AUC), together with vesselspecific optimal cut-off values, sensitivity, specificity, and 95% confidence intervals.

Because some patients contributed more than one vessel, observations were not completely independent. Therefore, diagnostic accuracy measures are presented as descriptive estimates, and results should be interpreted accordingly. Positive and negative predictive values were not emphasized because they may be influenced by the clustered nature of the data.

All statistical tests were two-tailed, and a p-value <0.05 was considered statistically significant. All patients were followed for six monthsforMACE, including death, myocardial infarction, and target vessel revascularization. Outcomes were recorded descriptively, as all treatment decisions were based exclusively on iFR, precluding comparative outcome analysis between diagnostic modalities.

3. Results

We analyzed 277 intermediate coronary lesions from 166 patients. The baseline clinical and lesion characteristics reflected a population with a substantial burden of cardiovascular risk factors, particularly diabetes mellitus and dyslipidemia, which were the most prevalent comorbidities. The distribution of age and sex across the three coronary territories showed a consistent male predominance, with men representing the majority of cases in all vessels. Age was relatively similar across LAD, LCX, and RCA lesions, indicating that vessel-specific differences in physiology were not driven by demographic variation (Table 1).

Table 1.

Baseline patient and lesion characteristics.

Characteristic	LAD	LCX	RCA
Sex, n (%)
Male	67	70	67
Female	33	30	33
Age (years)
Mean ± SD	53.3 ± 8.2	55.7 ± 8.9	56 ± 8.7
Risk factors, n (%)
Smoker	52	66	62
Diabetes mellitus	55.5	71.6	63.6
Hypertension	60.7	55.2	50.9
Dyslipidemia	78.1	82.1	92.7
Known IHD	35.5	56.7	50.9
Previous PCI	28.4	52.2	43.6
Family history of CAD	41.3	37.3	32.7
On regular medical therapy	31.6	47.8	47.3
Clinical presentation, n (%)
Acute presentation	3.2	4.4	9.1
Chest pain	90	91	98
Dyspnea	44	54	53
Ejection fraction (%)
Mean ± SD	50.9 ± 5.2	47.6 ± 5.4	49 ± 5.5
Number of lesions per vessel, n (%)
One lesion	58	60	36
Two lesions	40	21	59
Three lesions	2	13	5
Four lesions	0	6	0
Lesion site, n (%)
Proximal	28.3	26.8	34.6
Mid	63.9	41.8	43.6
Distal	5.8	10.5	18.2
Side branch	1.9	21	3.6
Lesion morphology, n (%)
Simple	73.6	80.6	83.6
Bifurcation	25.8	17.9	16.4
Ostial	0.7	1.5	0

Quantitative angiographic measurements demonstrated that the anatomical severity of disease was broadly comparable across vessels. The average diameter stenosis fell within the mid-50% range, consistent with an intermediate-stenosis cohort. Lesion length showed modest variation, with RCA lesions tending to be slightly longer, while minimal lumen diameter and minimal lumen area were relatively similar across territories. These findings confirm that the anatomical substrate of disease was not markedly different between LAD, LCX, and RCA lesions, providing a uniform baseline for evaluating physiological behavior (Table 2).

Table 2.

Quantitative coronary angiography and procedural characteristics.

Characteristic	LAD	LCX	RCA
Lesion length (mm)	16.2 ± 9.4	17.7 ± 8.2	20.6 ± 9.5
MLD (mm)	1.9 ± 2.1	1.8 ± 0.9	1.8 ± 0.5
Procedure duration (min)	45.9 ± 33.3	47.8 ± 27.6	49.2 ± 27.6
Diameter stenosis (%)	55 ± 10.7	52.5 ± 11.6	54.4 ± 11.4
iFR	0.85 ± 0.13	0.88 ± 0.13	0.85 ± 0.10

When operators’ QCA-based impressions were compared with final iFR-guided decisions, a distinct vessel-specific pattern emerged. LCX lesions showed the strongest alignment with iFR deferral, indicating greater confidence in recognizing non-significant LCX disease angiographically. RCA lesions demonstrated the highest concordance for proceeding with PCI, reflecting a tendency to judge RCA stenoses as physiologically important. In contrast, LAD lesions accounted for most discordant cases, underscoring the well-known difficulty of assessing intermediate LAD disease by angiography alone. Overall agreement between QCA-based and iFR-guided decisions was 75.5% for LAD, 85.1% for LCX, and 78.2% for RCA, with the LAD exhibiting the highest discordance rate (24.5%) compared with LCX (14.9%) and RCA (21.8%) (Table 3).

Table 3.

Concordance and Discordance of Revascularization Decisions (QCA vs iFR agreement).

	LAD	LCX	RCA
Similar decisions (No PCI)	40 %	52.2 %	36.4%
Similar decisions (Progress to PCI)	35.5 %	32.8 %	41.8 %
Different decisions	24.5 %	14.9 %	21.8 %

The diagnostic performance of QCA in predicting physiologically significant stenosis varied substantially by vessel. LCX demonstrated the strongest discrimination, with an AUC approaching 0.80, indicating a relatively good ability of anatomical stenosis to reflect physiological impairment in this territory. RCA performance was moderate, with an AUC slightly above 0.70. LAD showed the weakest performance, with an AUC in the mid-0.60 range, underscoring the limited reliability of angiographic stenosis in predicting functional severity in LAD lesions. These differences emphasize that the relationship between anatomical narrowing and physiological impact is vessel-dependent (Table 4; Figs. 2 and 3).

Table 4.

Diagnostic Performance of 2D-QCA for Predicting iFR (ROC analysis).

Vessel	Accuracy/AUC (%)	Cut-off (%)	P value	Sensitivity (%)	Specificity (%)	95% CI
LAD	66.6	53.5	<0.001	63.2	65.8	0.580–0.752
LCX	78.5	50.5	<0.001	72.0	69.0	0.673–0.897
RCA	72.2	52.5	<0.005	62.1	65.4	0.587–0.857

Note: CI, confidence interval; LAD, left anterior descending artery; LCX, left circumflex artery; RCA, right coronary artery.

Fig. 2.

Per-vessel ROC Curves for QCA Predicting iFR Outcome

Receiver operating characteristic curves for LAD, LCX, and RCA demonstrating the discriminative ability of QCA stenosis severity to predict physiologically significant ischemia defined by iFR ≤0.89.

Fig. 3.

Summary of ROC Analysis for QCA and iFR.

ROC analysis showing optimal QCA cutoff (52.6% stenosis; AUC 0.706) and iFR cutoff (0.89; AUC 1.000) for predicting ischemia. QCA sensitivity and specificity were 65.1% and 66.5%, respectively, while iFR achieved perfect discrimination by definition.

The relationship between stenosis percentage and iFR demonstrated wide scatter, with substantial overlap between physiologically significant and non-significant lesions. Several lesions with only moderate angiographic narrowing exhibited low iFR values, indicating physiologically important flow limitation. Conversely, some lesions with higher stenosis percentages remained physiologically non-significant. This pattern reinforces the limited predictive value of angiographic stenosis alone and illustrates why intermediate lesions frequently require physiological assessment when available and feasible (Fig. 4).

Fig. 4.

Scatter Plot of Stenosis Area vs iFR Across Coronary Vessels

Scatter plot demonstrating the relationship between anatomical stenosis severity and physiological significance across LAD (red), LCX (blue), and RCA (green). The dashed horizontal line marks the iFR threshold of 0.89. The wide dispersion highlights the limited correlation between stenosis percentage and functional ischemia.

During the six-month follow-up period, MACE occurred in 16.8% of LAD lesions, 6.0% of LCX lesions, and 9.0% of RCA lesions (Table 5). As treatment decisions were based exclusively on iFR findings, these outcomes are presented descriptively and were not compared according to QCA classification.

Table 5.

Six-month major adverse cardiovascular events (MACE).

Coronary vessel	Total lesions (n)	MACE, n (%)
LAD	155	26 (16.8)
LCX	67	4 (6.0)
RCA	55	5 (9.1)
Total	277	35 (12.6)

4. Discussion

Accurate assessment of coronary lesion severity is essential for appropriate vessel selection in revascularization procedures. Nevertheless, no single method can simultaneously provide both anatomic and functional data for optimal management of intermediate lesions.

Previous studies using physiological guidance have demonstrated that reserving revascularization for lesions with proven ischemia reduces peri-procedural myocardial infarction, procedure-related complications, in-stent restenosis, and stent thrombosis. Moreover, physiology-guided revascularization has been shown to be cost-effective, with pressure-wire—based assessment offering a rapid, simple, and lesion-specific measure of ischemia to guide clinical decision-making [17,18].

To our knowledge, the present study represents the first direct, vessel-specific evaluation by 2D-QCA parameters, specifically stenosis area for the prediction of functional significance in angio-graphically intermediate coronary lesions, using instantaneous wave-free ratio (iFR) as the reference standard. The study’s distinctive design incorporated analysis of the three principal epicardial coronary arteries individually, consideration of multiple lesions within the same vessel (excluding true tandem lesions), and integration of stenosis area as a classification parameter, thus addressing some of methodological gaps in prior literature.

Our principal findings indicate moderate diagnostic performance of 2D-QCA when benchmarked against iFR, with notable heterogeneity between coronary territories. The left circumflex artery (LCX) exhibited the highest diagnostic accuracy (AUC 78.5%), followed by the right coronary artery (RCA) (AUC 72.2%), while the left anterior descending artery (LAD) demonstrated the lowest accuracy (AUC 66.6%). Optimal vessel-specific stenosis area thresholds were 50.5% for LCX, 52.5% for RCA, and 53.5% for LAD, with corresponding sensitivities of 72.0%, 62.1%, and 63.2% and specificities of 69.0%, 65.4%, and 65.8%, respectively (Table. 4).

4.1. Comparison with Existing Literature (Table. 6)

Table 6.

Comparison of QCA diagnostic accuracy across studies.

Study (year)		Lesion (n)	Accuracy OR (AUC)	Sens.	Specif.	Comparison between
Our results 2025	LAD	155 IL	MLA 53.5% →66.6 %	63.2 %	65.8 %	2D-QCA VS IFR (0.89)
	LCX	67 IL	MLA50.5% →78.5 %	72 %	69 %
	RCA	55 IL	MLA 52.5 % →72.2 %	62.1 %	65.4 %
Bartúnek ET AL, 1995 [21]		157 IL	MLD <1.5 mm → 92%	96%	89%	2D-QCA VS FFR (0.72) (NON SELECTIVE COHORT)
			DS >50% →89%	93%	85%
Saad et al., 2009 [23]		41 IL	DS >45% → 93%	88.9%	87.5%	3D-QCA VS FFR (0.75)
			CSS >57% → 93%	88.9 %	90.6 %
Young et al., 2011 [22]		63	MLA 1.6MM2 → 81%	80%	79.2%	3D&2D -QCA VS FFR (0.75) (NON SELECTIVE COHORT)
			MLD 1.2 MM → 72%	75%	66.7%
Xu et al., 2017 [19]		332 IL	DS ≥ 50% → 64%	49.6%	72.2%	2D-QCA & QFR VS FFR (0,8)
Westra et al., 2018 [20]		317 IL	DS ≥ 50% → 65.9%	44.2%	76.5%

When contextualized within the existing body of work, the per-vessel performance observed for LAD lesions was comparable to that reported by Xu et al. and Westra et al. studies, both of whom employed FFR as the physiological reference. The superior accuracy in LCX and RCA lesions in our series may reflect differences in study design, particularly the exclusive inclusion of intermediate lesions and the adoption of iFR, which obviates hyperemia and may yield slightly different functional classification patterns [19,20].

Conversely, our accuracies were lower than those described by Bartúnek et al. and Young et al. studies, most likely due to their inclusion of non-selective cohorts encompassing mild lesions with larger minimal lumen diameters (MLDs), which tend to increase classification accuracy by widening the separation between physiologically positive and negative lesions [21,22].

The higher accuracies reported by Saad et al. are plausibly attributable to their use of three-dimensional QCA (3D-QCA), which offers superior spatial resolution and volumetric reconstruction of lesion morphology. Additionally, their patients population had less severe stenoses (mean DS 49.2 ± 13.4%) and a relatively low prevalence of functionally significant disease (only 9/41 lesions with FFR ≤0.75), both of which may enhance apparent diagnostic performance [23]. Young et al. study also, demonstrate that no statistically significant difference between 2D and 3D QCA overall, but noted a non-significant trend towards greater accuracy for 3D-QCA in intermediate lesions, These findings further support the continued role of conventional 2D-QCA in resource-limited settings because of its lower cost, widespread availability, and shorter procedural time compared with 3DQCA [22].

4.2. Contemporary context of 2D-QCA in the era of angiography-derived physiology

Since completion of the present study, coronary physiology has evolved substantially. Several angiography-derived physiological indices, including quantitative flow ratio (QFR), vessel fractional flow reserve (vFFR), and FFRangio, have emerged as attractive alternatives for functional lesion assessment. Unlike conventional 2D-QCA, these techniques integrate anatomical information with computational fluid dynamic modeling to estimate physiological significance without pressure-wire instrumentation or pharmacological hyperemia. Recent studies have demonstrated that angiography-derived physiology provides superior agreement with invasive FFR and iFR compared with anatomical stenosis assessment alone, with diagnostic accuracies frequently exceeding 80–85% [14,16]. (Table 7).

Table 7.

Evolution of coronary physiological assessment techniques.

	Method	Hyperemia	Pressure wire	Diagnostic basis	Contemporary role
1	2D-QCA	No	No	Anatomical	Widely available
2	FFR	Yes	Yes	Physiological	Reference standard
3	iFR	No	Yes	Physiological	Guideline-supported
4	QFR	No	No	Computational physiology	Emerging
5	vFFR	No	No	Computational physiology	Emerging
6	FFRangio	No	No	Computational physiology	Emerging

The FAVOR III China trial demonstrated that QFR-guided PCI resulted in significantly lower rates of major adverse cardiovascular events compared with angiography-guided PCI. Furthermore, contemporary validation studies of vFFR and FFRangio have consistently shown good diagnostic agreement with invasive physiological measurements [13,15].

Nevertheless, important barriers remain. Dedicated software platforms, image acquisition requirements, operator expertise, and licensing costs may limit widespread implementation, particularly in low- and middle-income healthcare systems. Consequently, conventional 2D-QCA continues to represent the most accessible angiographic quantification tool in many catheterization laboratories worldwide. The present study should therefore be interpreted not as a comparison with contemporary angiography-derived physiology but rather as an evaluation of whether widely available 2D-QCA can improve anatomical assessment beyond routine visual estimation when invasive physiological assessment is unavailable or impractical.

4.3. Explanations for vessel-specific performance

The superior LCX performance in our analysis may be attributable to the higher proportion of physiologically non-significant lesions (62.7% by iFR) in this vessel, thereby reducing false-positive classifications. LAD lesions are often longer, more tortuous, and more frequently eccentric features that reduce 2D-QCA measurement fidelity while also having a higher prevalence of true physiological significance, making accurate prediction inherently more challenging. RCA lesions, in this study, demonstrated intermediate morphological and functional complexity, producing accuracy metrics between those of LCX and LAD. Also, lower accuracy rate of LAD may be explained with higher number of lesions studied as compared with LCX and RCA lesions.

4.4. Methodological determinants of 2D QCA diagnostic accuracy

Several deliberate procedural refinements likely contributed to the relatively favorable diagnostic performance observed compared with earlier 2D-QCA reports:

• Projection Optimization: Angiographic imaging was obtained using views that minimized foreshortening and vessel overlap, maximizing geometric fidelity.

• Precise Lesion Co-registration: QCA measurement sites were exactly matched to iFR interrogation points, a critical consideration in vessels with serial lesions where gradual pressure loss can otherwise confound correlation analyses.

• Contemporary Imaging Systems: The use of a modern QCA platform with automated pixel calibration and high spatial resolution likely improved contour delineation and lumen measurement precision.

• Exclusion of Complex Bifurcations: Medina type 1,1,1 and 1,0,1 bifurcation lesion was excluded to avoid side-branch—related variability not adequately addressed by conventional QCA algorithms.t

4.5. Pathophysiological correlates

Consistent with prior physiological and histopathological evidence, stenosis area and minimal lumen area (MLA) correlated more robustly with functional significance than did percentage diameter stenosis. This is physiologically intuitive, as flow limitation is more directly determined by cross-sectional area than by linear diameter reduction. Histological studies have established that angiographic stenosis often becomes apparent only when plaque burden exceeds approximately 40–50% of the vessel cross-sectional area. Moreover, Young et al. highlighted that lesion eccentricity disproportionately impairs the correlation between QCA and FFR, an effect mitigated—but not eliminated by using stenosis area in lieu of diameter stenosis as the primary index [17].

4.6. Clinical implications

From a pragmatic standpoint, the present findings support a selective role for conventional 2D-QCA in triaging intermediate coronary lesions for invasive physiological assessment, particularly in resource-limited settings where pressure-wire systems, hyperemic agents, or procedural resources may be limited. Vessel-specific stenosis area thresholds may help identify lesions most likely to benefit from physiological interrogation, potentially reducing unnecessary pressure-wire assessment, procedural time, radiation exposure, and contrast use while maintaining acceptable diagnostic accuracy for many intermediate lesions.

However, the moderate diagnostic performance observed across all coronary territories—particularly in the LAD—precludes the use of 2D-QCA as a standalone decision-making tool. Reliance on anatomical assessment alone may result in both unnecessary revascularization of physiologically non-significant lesions and inappropriate deferral of ischemia-producing stenoses. The weak anatomical—physiological correlation observed in LAD lesions further emphasizes this limitation. Accordingly, iFR or FFR should remain the preferred strategy for physiological lesion assessment whenever available, with 2D-QCA serving as an adjunctive tool when pressure-wire assessment is unavailable, contraindicated, or not feasible because of resource constraints [24,25].

The higher incidence of MACE observed in LAD lesions during follow-up is consistent with the larger myocardial territory supplied by the LAD and the greater frequency of anatomically—physiologically discordant intermediate lesions in this vessel. Because all revascularization decisions in the present study were guided exclusively by iFR, these outcomes should be interpreted as reflecting underlying disease burden and vessel-specific risk rather than differences in the diagnostic strategy itself.

4.7. Study limitations

This study has several limitations. First, it was conducted only at two experienced tertiary centers, which may limit the generalizability of the findings and warrants validation in larger multicenter cohorts. Second, the study used a non-randomized design, and physiological assessment was restricted to intermediate lesions, while left main disease and lesions with <40% or >80% diameter stenosis were excluded, limiting applicability to these subsets. Third, a proportion of patients had a history of myocardial infarction, which may have influenced physiological measurements. Fourth, the study evaluated conventional 2D-QCA rather than newer angiography-derived physiological technologies, such as QFR, vFFR, and FFRangio, which have demonstrated superior diagnostic performance in contemporary studies [13,14]. Moreover, because the study was conceived before the widespread adoption of these computational physiology platforms, direct comparison with such technologies was beyond its scope. Finally, the moderate diagnostic performance observed across all vessels highlights the inherent limitations of anatomical assessment alone, which cannot fully account for the complex interactions among lesion geometry, coronary flow dynamics, microvascular resistance, and myocardial territory at risk [24,25]. In addition, although analyses were performed at the vessel level, some patients contributed more than one vessel. Consequently, observations were not entirely independent, and clustering was not explicitly modeled in the statistical analysis. Clinical decisions were guided by iFR, and therefore the study was not designed to evaluate clinical outcomes associated with a QCA-based strategy.

4.8. Future directions

Future investigations should directly compare conventional 2D-QCA with contemporary angiography-derived physiological technologies such as QFR, vFFR, and FFRangio to better define the role of anatomical assessment within modern coronary physiology practice. Multicenter studies incorporating diverse lesion morphologies and outcome-based endpoints are needed to determine whether QCA-guided triage strategies can enhance procedural efficiency while maintaining clinical safety. Evaluating QCA-guided versus physiology-guided revascularization strategies using both clinical outcomes and procedural metrics would further clarify real-world applicability. Integration with emerging angiography-derived physiology methods may also refine the anatomical—functional interface in lesion assessment.

5. Conclusion

In conclusion, this study demonstrates that 2D-QCA is a practical and cost-effective adjunct for refining angiography-based assessment of intermediate coronary lesions (40–80%). Its widespread availability and simplicity may support more informed decision-making in settings where invasive physiological assessment (iFR or FFR) is unavailable, contraindicated, or resource-limited, thereby reducing procedural burden and time.

Importantly, the diagnostic performance of 2D-QCA improved with increasing stenosis severity, with higher accuracy, sensitivity, and specificity observed in lesions with a stenosis area of >60–80% compared with those of 40–60%. Nonetheless, overall performance remained moderate, and the weakest anatomical—physiological correlation—particularly in LAD lesions—highlights the limitations of relying solely on anatomical measurements.

Therefore, while 2D-QCA can assist in lesion triage and enhance angiographic interpretation, it should be regarded as a complementary tool, not a substitute for invasive physiological assessment, which remains the preferred strategy whenever available.