Secondary ventricular mitral regurgitation (MR) is a common valvular disorder resulting from ventricular dilation or dysfunction rather than primary leaflet abnormalities.1 Progressive left ventricular (LV) dilation and spherical reshaping displace the papillary muscles laterally and apically, increasing leaflet tethering forces and restricting systolic closure. Moreover, annular dilation and flattening reduce leaflet coaptation, while impaired LV contractility diminishes closing forces across the valve. This imbalance between tethering and closing forces leads to incomplete leaflet apposition and regurgitant flow into the left atrium during systole. Thus, the regurgitation reflects geometric distortion of the mitral apparatus secondary to LV remodeling rather than intrinsic leaflet pathology.

Moderate-to-severe regurgitation is present in approximately one-quarter to one-third of patients with chronic systolic dysfunction, depending on the population studied and the echocardiographic definitions applied.2 Its prevalence increases with progressive LV dilation, prior myocardial infarction, longer duration of heart failure, and inadequate reverse remodeling despite guideline- directed medical therapy (GDMT). Beyond its prevalence, secondary MR carries substantial prognostic implications. Numerous observational analyses have demonstrated that moderate-to-severe secondary MR is independently associated with increased all-cause and cardiovascular mortality, even after adjustment for LV ejection fraction and clinical markers of disease severity.3 The hemodynamic burden imposed by regurgitant volume increases left atrial and pulmonary venous pressures, promoting congestion, recurrent heart failure hospitalizations, and progressive right ventricular dysfunction. Patients with significant secondary ventricular MR also exhibit reduced functional capacity and poorer quality of life.

Historically, mitral valve surgery has been considered the main interventional approach for patients with significant secondary MR. Over the past few decades, several studies, including randomized clinical trials and meta-analyses, have evaluated the role of mitral valve surgery in this setting. These investigations showed that although surgery can reduce MR severity and, in some cases, promote reverse ventricular remodeling, evidence supporting a survival benefit vs optimal medical therapy alone remained limited.4 On the other hand, transcatheter interventions offer a less invasive alternative to open-heart surgery. Among these, percutaneous procedures, particularly transcatheter edge-to-edge repair (TEER), have been increasingly adopted. As supporting evidence grew accumulated, mitral TEER has been widely implemented in contemporary interventional practice worldwide. In recent years, 3 randomized clinical trials have compared GDMT plus mitral TEER with GDMT alone in patients with secondary significant MR. In a recent study published in REC: Interventional Cardiology, Paulino-González et al.5 conducted a systematic review and meta-analysis of the main clinical endpoints evaluated in randomized clinical trials comparing mitral TEER and optimal medical therapy thus far. They conducted a systematic search of electronic databases and identified 3 randomized clinical trials including more than 1400 patients overall. The primary endpoints were all-cause mortality and heart failure hospitalization. An exploratory analysis excluding patients from the MITRA-FR study6 was also performed to reduce heterogeneity between study populations. Overall, there was a trend towards lower all-cause mortality which did not meet statistical significance (risk ratio [RR], 0.80; 95% confidence interval [95%CI], 0.63–1.02; P = .07). Heart failure-related hospitalization rates were signifi- cantly lower among patients who underwent mitral TEER (RR, 0.71; 95%CI, 0.56-0.90; P = .004). In the exploratory analysis excluding MITRA-FR patients, both all-cause mortality (RR, 0.71; 95%CI, 0.59–0.86; P = .0005) and heart failure hospitalization (RR, 0.63; 95%CI, 0.55-0.72; P < .00001) were significantly reduced with the percutaneous approach, with minimal heterogeneity between studies. The reduction in the composite endpoint of heart failure-related hospitalization or death with mitral TEER was consistent among patients presenting grade 3+ and grade 4+ MR at baseline. There were no significant differences between mitral TEER and optimal medical treatment in terms of safety endpoints, including stroke and myocardial infarction.

Several aspects of this meta-analysis merit further consideration:

• – Differences in baseline clinical features across the included studies. When the COAPT trial7 was published in 2018, it provided compelling evidence that TEER reduced both heart failure-related hospitalizations and mortality in carefully selected patients with symptomatic heart failure and moderate-to-severe or severe secondary MR. Importantly, COAPT required rigorous optimization of GDMT before enrollment and objective confirmation of persistent, significant MR. In contrast, the MITRA-FR trial, reported in the same year, failed to demonstrate a reduction in death or heart failure-related hospitalization.6 At first glance, the results seemed contradictory to those of COAPT. However, closer examination reveals fundamental differences in trial design and patient phenotype. MITRA-FR applied broader MR severity thresholds and enrolled patients with substantially larger LV volumes. In these patients, MR severity was more proportionate to the degree of ventricular remodeling, suggesting that regurgitation was primarily a consequence, rather than a cause, of advanced myocardial disease.8 The RESHAPE-HF2 trial9 aimed to evaluate this comparison in a contemporary therapeutic landscape. Conducted in the era of more comprehensive GDMT, including greater uptake of sacubitril/valsartan, mineralocorticoid receptor antagonists, and SGLT2 inhibitors, its findings, showing reduction in heart failure events and symptomatic improvement, with a less pronounced mortality effect than COAPT), suggest that TEER may confer benefit across a broader spectrum of MR severity than that represented in COAPT, albeit with a smaller effect size.
• – Grades of residual MR after percutaneous intervention. As the authors stated in the discussion,5 MR reduction was less effective in the MITRA-FR trial. In conclusion, MR reduction to ≤ 2+ in MITRAFR (75.6% MR ≤ 2+ at discharge) was markedly lower than that obtained in COAPT (94.8% MR ≤ 2+ at 12 months) and the RESHAPEHF2 (90.4% MR ≤ 2+ at 12 months). In MITRA-FR the degree of MR reduction was modest relative to what has been observed in other studies, with many patients remaining with moderate residual regurgitation. Because baseline regurgitation in MITRA-FR tended to be less severe, based on effective regurgitant orifice area and regurgitant volume thresholds, and proportionate to LV dilation, the capacity of TEER to achieve a large absolute reduction in regurgitant volume was inherently limited. Analyses of residual MR in RESHAPE-HF2 suggest that the degree and durability of regurgitation correction remained an important determinant of clinical response: patients with sustained mild or lesser degrees of MR demonstrated the most favorable clinical outcomes, whereas those with persistent moderate regurgitation derived attenuated benefit.10 Additional factors may also have influenced trial outcomes, including increasing operator experience and advances in device technology over time. For example, the G4 generation of the MitraClip system (Abbott, United States) utilized in the RESHAPE-HF2 trial enables independent leaflet grasping and provides a wider range of device sizes, ultimately enabling tailored device selection potentially improving treatment of complex mitral valve anatomies.

Overall, Paulino-González et al.5 should be commended for their work and contribution to the field. Consistent with the findings of the abovementioned trials, this meta-analysis supports the fact that secondary ventricular MR is not merely an epiphenomenon of LV dysfunction but a modifiable contributor to adverse outcomes. Moreover, mitral TEER in combination to GDMT clearly constitute the best therapeutic strategy for improving clinical prognosis.

FUNDING

None declared.

CONFLICTS OF INTEREST

None declared.

REFERENCES

Thirty years ago, in 1996, the concept of evidence-based medicine took hold; David Sackett, one of its leading advocates, defined it as the conscientious, explicit, and judicious use of the current best evidence for clinical decision-making. Since then, the properly designed randomized clinical trial has been the method par excellence for demonstrating the efficacy of medical interventions and generating robust evidence to inform the recommendations of scientific societies. However, over the past few decades, the scientific community has learned a great deal about the limitations of this methodology.

The results of the OPTIMAL trial have recently been published; the trial was designed to determine whether intravascular ultrasound (IVUS)-guided percutaneous revascularization of the unprotected left main coronary artery (LMCA) leads to better clinical outcomes than revascularization guided by conventional angiography alone.1 In this trial, a total of 806 patients with a mean age of 71 years and a mean SYNTAX score of 30 were randomized to one of the two interventions; 78% of them were women. After a median follow-up of 2.9 years, the primary endpoint occurred in 135 patients (33.7%) in the IVUS-guided group and in 125 patients (30.9%) in the angiography-guided group. The incidence of death, myocardial infarction, or revascularization was similar in both groups. The incidence of stroke was higher in the IVUS group, although these events occurred at a median of 19 months, which may suggest a chance finding. The authors concluded that, among patients with LMCA disease, IVUS-guided percutaneous revascularization showed no additional benefit compared with angiography- guided revascularization. This is not the first time that trial results have conflicted with initial expectations.

For many years, I have been an advocate and promoter of the use of IVUS to guide drug-eluting stent angioplasty procedures in the LMCA, based on a conviction derived from my own experience, but primarily on the results of numerous observational studies, including some that we conducted in our country.2,3 Therefore, being one of the principal investigators and the second author of the OPTIMAL trial manuscript places me in a unique position. On the one hand, I must accept the results of a trial that was executed flawlessly in every respect; on the other hand, I remain convinced that the use of IVUS can continue to add value in many cases of LMCA disease, especially when used appropriately. In the following paragraphs, I will attempt to explain and justify this position (figure 1).

Figure 1. Various factors explaining the relative discrepancy between the expected results and those ultimately obtained in the OPTIMAL study. IVUS: intravascular ultrasound; LMCA: left main common artery; MSA: minimum stent area. The bibliographical references mentioned in this figure correspond to Testa et al.1 (OPTIMAL trial) and Holm et al.4 (OCTOBER trial).

EXPECTATIONS PRIOR TO THE OPTIMAL TRIAL

In recent years, several observational studies and corresponding meta-analyses have been published, all of which demonstrated that the use of IVUS in percutaneous revascularization of the LMCA was associated with a reduction in events, including cardiac death, myocardial infarction, and revascularization.5 However, it is evident that the benefits observed in registries are often exaggerated, and this is due to certain biases. First, selection bias. Comparing cases in which IVUS was used versus those in which it was not within a registry implies selection bias, since that decision was based on certain variables, which ultimately affected certain characteristics of the patients and the lesions. Even with statistical matching techniques, it is very difficult to completely eliminate the confounding effect of partially hidden biases.2 In this regard, the use of IVUS may have been more likely in patients in better clinical condition, who were more stable, and younger. This could explain the differences in overall mortality observed as early as the short- to medium-term between the IVUS and angiography groups in some registries.6

Another potential source of bias relates to the operator and the center. It is plausible that operators who used IVUS more frequently were also more meticulous in other technical and patient management aspects and were based at centers with higher patient volumes and greater experience. A large British registry found that the benefit of IVUS was greater when operators had higher case volumes, suggesting this bias.6

The positive results of some randomized trials, although not focused on the LMCA and conducted in Asian countries, also instilled considerable optimism.7-10

The OCTOBER trial, which compared optical coherence tomography-guided versus angiography-guided treatment of bifurcations, showed a lower incidence of the primary endpoint at 2 years (10.1% vs 14.1%).4 It should be noted that these were mostly bifurcations that did not involve the LMCA and involved smaller vessels, where a greater effect of small changes in the minimum stent area (MSA) on clinical outcomes is expected.

PATIENT PROFILE

In the OPTIMAL trial, the mean age of patients was 71 years, 5 years older than that of patients in the OCTOBER trial.1,4 Fifty-eight percent had three-vessel disease, with a mean SYNTAX score of 30. This explains the high incidence of events, exceeding 30% at 2.9 years.1

As is often the case in many trials, and especially when there are pre-existing biases, patient enrollment may have taken into account factors beyond the inclusion/exclusion criteria, leading to selection bias. Consequently, it is possible that some patients for whom IVUS was deemed necessary (such as those with more complex distal lesions or younger patients) were excluded.

CHARACTERISTICS OF LMCA LESIONS

In the OPTIMAL trial, 60% of the treated LMCA lesions involved the bifurcation. In a large Spanish multicenter registry, with two matched groups of 505 patients each, we found that the benefit associated with the use of IVUS in LMCA angioplasty with drug-eluting stents was greater in distal lesions and, particularly, in those requiring two stents.2 Therefore, the inclusion of a relatively high proportion of non-distal lesions may have reduced the overall impact of IVUS in the OPTIMAL study.

In the recently published IVUS-CHIP trial, which evaluated the use of IVUS in 2020 patients with complex lesions and demostrated no differences compared with angiography, a trend toward a benefit from IVUS was observed in distal LMCA lesions.11

THE IVUS GROUP

IVUS is not a therapeutic tool, it is an imaging technique, and the benefit it may provide depends on how the operator uses it. The resulting clinical advantage derived from its use will be solely due to the corrective measures prompted by the imaging findings, the optimization criteria pursued, and the extent to which those criteria are met. In the OPTIMAL trial, the use of IVUS prior to the procedure was 65%, whereas a higher rate of use would have been expected to better understand the characteristics of the plaques and plan plaque management.

Among the optimization criteria, those related to expansion are particularly relevant, specifically the MSA cutoff values that were considered mandatory to achieve in this trial.12 These values were 8 mm² for the LMCA, 7 mm² for the confluence polygon, 6 mm² for the left anterior descending artery, and 5 mm² for the left circumflex artery, which were acceptable at the time the trial was designed but have since been surpassed by more recent studies. Currently, the optimal MSA cutoff values are estimated at 10 mm² for the TCI, 7 mm² for the left anterior descending artery, and 6 mm² for the left circumflex artery.13-17 In fact, just as this editorial was being written, the European Association of Percutaneous Cardiovascular Interventions and the European Bifurcation Club published a consensus document on the use of imaging in LMCA angioplasty that incorporates these new target values.18

In the OPTIMAL study, the final MSA in the LMCA was 12.99 ± 4.09 mm², 7.79 ± 2.43 mm² in the left anterior descending artery, and 6.75 ± 1.92 mm² in the left circumflex artery, indicating that in 15% of cases the MSA in the LMCA was less than 9 mm², less than 5.3 mm² in the anterior descending artery, and less than 4.8 mm² in the circumflex artery.1

However, in addition to establishing criteria, it is advisable to attempt, within the bounds of what is feasible and safe, to achieve these objectives. In the OPTIMAL study, corrective actions were observed in 29.3% of cases, and optimization was confirmed in 73%, with a numerically lower event rate in the optimized group (31.7% vs. 35.1%).1 It should be noted that failure to achieve the targets cannot be attributed solely to lack of adherence but is often due to safety considerations. In this regard, it is noteworthy that there were no differences in periprocedural complications between the groups.

The consideration of appropriate criteria and their implementation under a standardized protocol provides a benefit compared to the non-protocolized use of IVUS.3

THE GROUP ASSIGNED TO ANGIOGRAPHY

Another striking aspect is the high degree of similarity between the groups regarding the technical aspects of the procedure, with a similar rate of post-dilatation and similar device sizes. This may suggest that the operator working solely with angiography acted based on the knowledge and experience of someone who has performed many IVUS-guided procedures, which could be considered an angiography- guided intervention but inspired by prior experience with IVUS.

In this regard, while we previously noted that Asian trials7-10 generally yielded more positive results than Western ones,1,11,19 it is worth noting that the angiography group in the former shows clear differences from the intravascular imaging group, with much lower use of post-dilatation and selection of stents with significantly smaller diameters. It is likely that the very high use of IVUS in Asian countries may influence this different approach when angiography is the only option available. Furthermore, it cannot be ruled out that these operators adhered more strictly to the protocol for optimization based on intravascular imaging.

FINAL COMMENTS AND RECOMMENDATIONS

Further subgroup analyses of the OPTIMAL trial are needed to address issues such as the effect of IVUS in cases of isolated LMCA disease, to explore outcomes based on different MSA values, and, above all, to identify anatomical or clinical subgroups that benefit most from IVUS-guided procedures.

The conclusions drawn from these reflections are as follows:

• –The routine use of IVUS to guide percutaneous revascularization in all cases of LMCA lesions is not clinically justified when operators have sufficient experience in performing the procedure.
• – It is necessary to identify which LMCA lesion profiles benefit most from the use of intravascular imaging techniques (most likely distal lesions).
• – Appropriate optimization criteria should be established.
• – Efforts should be made to achieve these objectives within safety margins.
• – The implementation of automated intravascular image assessment systems (based on artificial intelligence) can be of great help in this regard.
• – It is essential to continue promoting training and the use of intravascular imaging techniques among less experienced professionals.

Finally, in my opinion, it would be advisable to conduct a new randomized trial that includes patients with distal LMCA lesions without a high SYNTAX score and uses the most up-to-date optimization criteria.

“Science never offers absolute certainties; rather, it is a dynamic process of conjecture and refutation.”

Karl Popper

FUNDING

No funding was received for the preparation of this manuscript.

CONFLICTS OF INTEREST

J.M. de la Torre-Hernández is the editor-in-chief of REC: Interventional Cardiology; the journal’s editorial procedure to ensure impartial handling of the manuscript has been followed. J.M. de la Torre-Hernández is a member of the steering committee of the OPTIMAL study and discloses payments from Abbott, Medtronic, Philips, Biotronik, Amgen, Daiichi Sankyo, Boston Sci, and Novartis as a speaker and consultant.

REFERENCES

To the Editor,

Evaluation of chest pain remains a frequent clinical challenge, with ongoing debate surrounding the optimal diagnostic strategy. Among the available modalities, coronary computed tomography angiography (CCTA) has emerged as a reliable diagnostic imaging modality because of its high sensitivity and negative predictive value. However, its positive predictive value remains moderate (60%–70%) vs invasive coronary angiography (ICA) and stress imaging modalities. This limitation often results in increased downstream testing, as demonstrated by the PROMISE trial.1 Recent technological advancements have enabled non-invasive assessment of the hemodynamic significance of coronary lesions, allowing fractional flow reserve derived from computed tomography (FFR-CT) to be calculated directly from CCTA images without the need for pharmacological stress agents or additional radiation exposure. Previous prospective trials have demonstrated a significant enhancement in the diagnostic accuracy of FFR-CT vs CCTA alone. As a result, the United States, the United Kingdom and European clinical practice guidelines currently endorse the use of FFR-CT. However, uncertainties remain regarding its clinical effectiveness and cost-efficiency across different health care systems and clinical settings.

We evaluated the potential clinical and economic impact of integrating FFR-CT into the routine practice in Spain vs standard care in patients with moderate stenosis on coronary computed tomography angiography (CCTA). We conducted a retrospective, observational, single-center intervention simulation study including outpatients with stable chest pain who underwent CCTA from July 2021 through December 2022 at a Spanish university hospital. Eligible patients had lesions classified as CAD-RADS 2.0 grade 3 (50%–69% stenosis) in vessels ≥ 1.5 mm,2 body mass index (BMI < 35 kg/m²) and coronary artery calcium score < 1000 Agatston Units (AU). Patients were identified through administrative databases, and electronic health records were reviewed to collect baseline clinical and imaging data. CCTA reports were independently reviewed by 5 clinical cardiologists, who recommended additional tests or treatments according to their clinical judgment. The same process was repeated after incorporation of FFR-CT to determine how functional information influenced decision-making. For each scenario, cardiologists answered questions, both before and after FFR-CT analysis: a) What additional diagnostic tests would you request? b) Would you recommend hospital admission, outpatient management, or discharge? c) What treatment strategy would you propose? d) Was the FFR-CT information useful? (figure 1). This structure enabled direct comparison of anatomical-only decisions vs those incorporating functional data. Significant FFR was defined as at least 1 vessel with FFR ≤ 80%.

Figure 1. Study design and outcomes. CAD-RADS, coronary artery disease-reporting and data system; CT, computed tomography; FFR, fractional flow reserve; ICA, invasive coronary angiography; MRI, magnetic resonance imaging.

CCTA images were acquired using a dual-source scanner (Somatom Drive, Siemens Healthineers, Germany) and interpreted by cardiologists and cardiovascular radiologists. FFR-CT analysis was performed by experts blinded to the original CCTA findings using DEEPVESSEL-FFR (Keya Medical Technology Inc; China), a new machine learning-based software platform that uses artificial intelligence and deep learning algorithms to generate FFR-CT values directly from CCTA datasets.3

The primary endpoint was total cost generated or saved after incorporating FFR-CT. Secondary endpoints included changes in tests utilization, hospitalizations decisions, adjustments in optimal medical therapy and physician-perceived satisfaction after FFR-CT analysis.

Baseline characteristics are expressed as frequencies and percentages for categorical data, and as mean ± standard deviation for continuous data. A cost analysis assessed the financial impact of the clinical decisions made in the intervention simulation, calculating total costs generated or avoided accordingly. Reference prices were obtained from our regional health care system and updated to 2024 using the Consumer Price Index.4 The company-reported cost of each FFR-CT analysis was €400. All statistical analyses were performed using Stata 16.1; P values <.05 were considered statistically significant.

Among 631 outpatients who underwent CCTA, 43 (6.8%) met the inclusion criteria. Most were men, with a mean age of 64.7 ± 8.6 years. The mean Agatston score was 355.7 AU, reflecting a high coronary calcium burden. Dyslipidemia and hypertension were present in fewer than one-half of patients, and diabetes was documented in 11 (25.6%). The mean body mass index was 27.6 ± 4.3 kg/m², and mean radiation exposure was low (1.9 ± 1.1 millisievert). A total of 83.7% of patients underwent single-beat acquisition (Flash); 7%, prospective (‘step-and-shoot’) acquisition; and 9%, retrospective acquisition. FFR-CT analysis was not feasible in 3 cases (7%) due to motion artifacts. Among successful analyses, 5 patients (11.6%) had a positive FFR-CT result.

In the clinical simulation analysis, 215 clinical scenarios were finally evaluated, corresponding to the individual assessment of all 43 cases by each of the 5 participating cardiologists. Prior to FFR-CT, additional testing was recommended in 89.9%, based solely on CCTA findings. The most frequently requested imaging modalities were stress cardiac magnetic resonance (CMR) (n = 118; 54.8%), and ICA (n = 46; 21%). After FFR-CT, the need for further testing dropped down to 28% (P < .01), with marked reductions in stress CMR (to 12%, -78%; P < .01) and ICA (to 15%, -26%; P < .01), respectively (table 1). This shift resulted in notable cost savings: total diagnostic costs decreased from €301 690 to €255 720, yielding savings of €45 976.64 (€213.84 per case). Discharge recommendations increased from 11% to 48% after FFR-CT (P <.01). Clinicians found FFR-CT helpful in 81% of scenarios. There were no significant changes in decisions regarding medical therapy.

Table 1. Cost analysis based on clinical simulation analysis

Complementary tests	Before CT-FFR, N (%)	Total cost (CT + additional testsa), €	After CT-FFR, N (%)	Total cost (CT + CT-FFR + additional testsa,b), €	P	Balance, €
ICA	46 (21)	80 865.99	32 (15)	69 024.64	< .01
SPECT	9 (4)	9180.98	1 (0.5)	1420.11	.01
Stress MRI	118 (55)	183 383.24	25 (12)	48 850.50	< .01
Stress echo	19 (8)	17 601.98	2 (0.9)	2652.04	< .01
No test	23 (10)	10 649.92	155 (72)	133 768.1	< .01
Total		301 692.04		255 715.4		45 976.64
CT, computed tomography; FFR, fractional flow reserve; ICA, invasive coronary angiography; MRI, magnetic resonance imaging; SPECT, single photon emission computed tomography. a Cost Regional Healthcare system December 2024 (updated to 2024 values based on the Consumer Price Index) (€): ICA = 1294.95; SPECT = 557.09; Stress MRI = 1091.16; CTA = 463.02; Stress echo = 463.40 b The cost of CT-FFR was estimated at € 400 per study.

This intervention simulation study provides several clinically relevant insights. First, FFR-CT was associated with lower health care spending and fewer downstream testing. Second, it enabled completion of the diagnostic process in a high proportion of patients and was judged clinically useful in most cases. As the first study in Spain evaluating an FFR-CT–guided strategy, it suggests that routine implementation could decrease downstream investigations and associated costs in patients with stable chest pain.

Most cost-efficiency data comes from the United States and the United Kingdom, where FFR-CT adoption is higher. While in the United States, the PLATFORM study demonstrated cost reductions, primarily driven by decreased use of ICA,5 evidence from the United Kingdom is more heterogeneous. While the latest NICE update projected £391 savings per patient, Mittal et al. reported higher costs vs stress imaging, although these findings have been questioned because most patients had stenoses outside the 50%–69% range—where additional testing and interobserver variability are more frequent—and the observed cost increase was largely attributable to higher ICA rates, findings that contradict earlier reports.6 In our cohort, stress CMR (54.8%) and ICA (21%) decreased substantially after incorporation of FFR-CT (to 12% and 15%), resulting in savings of €213.84 per case.

In addition, FFR-CT effectively concluded the diagnostic process, increasing the discharge rate from 11% to 48% after FFR-CT (P < .01). This notable finding introduces an important dimension of organizational efficiency, as it may help optimize imaging resources and reduce waiting times for advanced diagnostic tests. Notably, previous cost evaluations have primarily focused on avoidance of unnecessary testing, and have not fully captured this potential management benefit. Furthermore, clinicians participating in the study considered FFR-CT highly useful in 87% of cases.

The main limitation of our study is its simulation-based design. Economic outcomes were influenced by local test utilization patterns and regional pricing structures, which may limit external validity and generalizability. Therefore, the results should be considered hypothesis-generating.

In conclusion, in this simulation study, incorporation of FFR-CT in patients with stable chest pain and moderate coronary stenosis on coronary CCTA was associated with reduced downstream testing, lower health care costs, and higher discharge rates within the Spanish National Health System.

DATA AVAILABILITY

The data underlying this study will be made available upon reasonable request. Requests should be directed to the corresponding author.

FUNDING

None declared.

ETHICAL CONSIDERATIONS

This study was conducted in full compliance with the principles outlined in the Declaration of Helsinki and the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines on clinical research. As this was an interventional simulation study based on previously collected and fully anonymized data, formal ethical approval and informed consent were deemed unnecessary. Although this study included male and female patients alike, sex disaggregated analyses were not performed due to lack of expected sex related differences.

STATEMENT ON THE USE OF ARTIFICIAL INTELLIGENCE

No artificial intelligence has been used in the development of this paper.

CONFLICTS OF INTEREST

None declared.

AUTHORS’ CONTRIBUTIONS

Conceptualization, formal analysis, drafting of the original manuscript, and supervision were performed by J.A. Parada-Barcia and M. Barreiro-Pérez. Critical review and editing of the manuscript were undertaken by the remaining authors. All authors approved the final version of the manuscript for publication and accept all aspects of the work.

REFERENCES