Functional assessment of intermediate coronary stenoses by means of fractional flow reserve (FFR) has proven to be better than angiography alone in selecting lesions to be treated and in guiding percutaneous coronary intervention (PCI) [1, 2, 3]. In contrast, intracoronary imaging techniques, such as optical coherence tomography (OCT), despite useful in optimizing PCI, does not still play a clear role when it comes to choosing the lesions to treat [4, 5, 6]. The open-label, single-centre, prospective, randomized “FFR or OCT Guidance to Revascularize Intermediate Coronary Stenosis Using Angioplasty” (FORZA) trial [7] (NCT01824030) was therefore conducted in order to compare the clinical and economic implications of PCI-deferral of angiographically intermediate coronary lesions (AICLs) based on OCT evaluation or on FFR assessment. In the present report, the 24-months follow-up results of the subgroup of patients in which a strategy of FFR or OCT guided strategy of PCI deferral of the FORZA trial are presented.

The characteristics of the patients and lesions enrolled in the two study arms are showed in Tables 1,2 [8]. In the FFR group, PCI was deferred in 119 patients (67.6%) vs 82 (47.1%) in the OCT group. Deferred patients according to FFR or OCT were fairly similar (no statistically significant difference in baseline clinical characteristic except for a significant higher statin and oral anticoagulation use in patients evaluated by OCT). In the OCT group, higher prevalence of multivessel disease and LCX involvement were noted. Mean FFR was 0.87 $\pm$ 0.05 in deferred FFR group while mean minimal lumen area was 3.74 $\pm$ 1.94 mm${}^2$ and area stenosis 53 $\pm$ 18% in the deferred OCT group.

Bifurcation lesions were slightly more prevalent in the OCT arm, without significant differences in terms of prevalence and revascularization adopted strategy (single stent or double stents) (Table 3).

Radioscopic time, dose area product (DAP), consumption of contrast medium and postprocedural length of stay were numerically, but not significantly, higher in OCT than in FFR group (Table 4).

The two groups had a similar value of frequency of angina at SAQ at enrolment and both groups improved similarly at 24 months follow-up (from 82 $\pm$ 21 to 98 $\pm$ 7 in FFR, p 0.001 and from 87 $\pm$ 20 to 98 $\pm$ 5 in OCT, p 0.001; delta SAQ in FFR 16 $\pm$ 20 vs delta SAQ in OCT 10 $\pm$ 22, p = 0.09) (Table 5). More importantly, the prevalence of persisting significant angina (defined as 90 in frequency scale of SAQ) was similar in FFR and OCT deferred patients (5% vs 7.3%, p = 0.55) (Table 5). Overall, after 24 months of follow up after the index procedure with eventual PCI deferral, the rate of patients managed with optimal medical therapy alone was still significantly higher in FFR group in comparison to OCT (60% vs 44.2%, p = 0.004) (Fig. 3). As shown in Fig. 4, 24-month MACE were numerically (albeit not statistically significant) higher in FFR arm (10.9% vs 6.1%). Not significant differences were observed in terms of individual endpoints between groups (TVR 7.5% FFR vs 2.4% OCT, p = 0.20, MI 2.5% FFR vs 0% OCT, p = 0.27, death 2.5% FFR vs 3.7% OCT, p = 0.68) (Figs. 4,5). Such additional events caused further hospitalizations and procedures during the 24 months follow-up so that costs (which were significantly lower at baseline with FFR) were not statistically significant different between the FFR and OCT deferred patients at 24 months (2904 $\pm$ 2028 vs 3387 $\pm$ 2092 euros, p = 0.10) (Fig. 6).

Fig. 3.

Rate of patients managed with optimal medical therapy alone. FFR, fractional flow reserve; OCT, optical coherence tomography.

Fig. 4.

Prevalence of different endpoints and Kaplan Meier curves for MACE. MACE, major cardiovascular events; SAQ, Seattle Angina Questionnaire; FFR, fractional flow reserve; OCT, optical coherence tomography.

Fig. 5.

Kaplan Meier curves for Death, myocardial infarction (MI) and Target vessel revascularization (TVR). Panel A (Death), Panel B (MI) and Panel C (TVR).

Fig. 6.

Costs for patients managed with FFR and OCT at baseline and at 24-month follow-up (in euros). FFR, fractional flow reserve; OCT, optical coherence tomography.

A strategy of safe deferral of revascularization is possible only when spontaneous cardiovascular events are lower than the predicted events due to the procedure. A large body of evidence supports the safety of PCI deferral in case of FFR $>$0.80 [1] and current guidelines on PCI recommend the use of FFR (or instantaneous wave-free ratio) to assess the hemodynamic relevance of intermediate-grade coronary stenoses. On the contrary, data on clinical outcomes associated with deferral of PCI based on OCT findings are scarce and no standard anatomic references are described to evaluate the relevance of intermediate stenoses. Thus, we performed a novel analysis of the FORZA trial after an extended follow-up time of 24 months, comparing the subgroup of patients in which PCI was originally deferred based on FFR or OCT.

So far, we observed that FFR was associated with lower costs and higher medical management rate while OCT reduced the composite endpoint of major adverse cardiac events (MACE) or significant angina at 13-month [9, 10].

At 24-month of follow up FFR was still associated with a larger number of conservatively treated lesions translating into a larger and significantly higher number of medically managed patients. The high medical management rate and the overall low number of events confirmed FFR as the best and safe strategy to defer PCI.

On the other hand, the higher rate of performed PCI in the OCT arm was in line with the old previous studies, showing that visual assessment at the angiography [2], as well anatomical findings obtained by IVUS, were constantly associated with a higher rate of anatomically significant stenosis in comparison to functionally significant stenosis according to FFR.

Differently from what initially assumed in the main paper regarding the safety of “conservative” OCT criteria, a non-significant difference of MACE between the functional and imaging deferred arms was documented, with numerically less events in the OCT group.

In details, a similar death rate and a less rate of MI and TVR in OCT patients were detected underling the ability of imaging evaluation to characterize the natural history of coronary lesions, excluding the presence of high-risk features of untreated plaques and resulting a safe technique to defer PCI without impact on patient’s prognosis. On the other hand, the non-significant increase in TVR and hospitalizations in FFR arm affected total costs, which became not more statistically different at extended follow up of 24 months.

A similar value of frequency of angina at SAQ and, more importantly, a similar prevalence of persisting significant angina was noted between two arms. These data disclosed the ability of the “conservative” OCT criteria to be associated with hemodynamic significance of lesions and to predict stenosis-related myocardial ischemia in a way like FFR. We suggested a new role of pre-PCI OCT: not only to characterize coronary lesions and correctly select PCI materials in a “imaging-guided PCI” but also as an acceptable alternative for deferral angioplasty in intermediate lesions.

This study represents the first evidence that an anatomical guidance using OCT imaging, applying the simple FORZA criteria, could be an acceptable alternative to the physiological reference standard also for deferral of AICLs.

These are the first data supporting the use of OCT to safely defer treatment of AICL taking FFR as the gold standard. Despite the quite limited number of patients enrolled in this sub-analysis of the FORZA trial could limit the ability to draw definitive conclusions about safety of OCT to safely defer treatment of AICL, the numerically lower rate of event seen in comparison to FFR seems quite reassuring. We believe that an imaging evaluation of intermediate coronary lesions could be a comparable strategy to defer PCI like FFR, and at the same time we suppose a possible link between morphologic plaque assessment and hemodynamic significance of lesions in order to predict stenosis-related myocardial ischemia. We strongly support further investigations in this field, in particular more data are needed to assess the correlation between anatomical and functional indexes in order to predict MACE and myocardial ischemia.

Our data derived from a single centre study, with a small sample size and the result should be regarded as hypotheses generating. It was conducted locally without either a structured clinical research organization or an independent clinical events committee. The use of unconventional OCT criteria has to be acknowledged in light of the lack of clear data at the time of design of the trial [7]. However, after initiation of the study, these criteria were validated in comparison to FFR in a retrospective cohort of patients assessed with both FFR and OCT [11] and a recent randomized trial showed a safe profile of the OCT criteria to defer or perform PCI [12]. FFR assessment was made in according to the best clinical practise, however a clear definition of diffuse versus focal disease was not available because of the absence of new tools (PPG index) [13] at the start of the study. However, pullback manoeuvres were performed both in the pre and post PCI phase to assess the pressure drop distribution along the vessel. Total procedural time was not recorded but we evaluated the “procedural radioscopic time” as a surrogate, less dependent by logistic or procedural confounders.

The 24-months follow-up results of the FORZA trial, the first prospective randomized trial comparing OCT and FFR to guide PCI decision and performance in AICLs, showed that deferral of PCI based on OCT is clinically safe as compared with the (contemporary gold-standard) FFR-guided approach. Over 2 years, FFR-guidance warranted higher rate of optimal medical therapy management alone as compared with OCT-guidance.

AML and FBur—conception and design, analysis and interpretation of data, drafting, and revising critically the manuscript for important intellectual content; CA and DG—analysis of data and drafting of the manuscript; GZ, AZ, FDG, FBia and RV—collection, analysis, and interpretation of data; CT and FC—important intellectual contribution; All authors contributed to the article and approved the submitted version.

The studies involving human participants were reviewed and approved by Comitato Etico del Policlinico Gemelli di Roma (number 6261/13). The patients/participants provided their written informed consent to participate in this study.

We would like to express our gratitude to the peer reviewers for their opinions and suggestions, and to all those who helped us with writing of this manuscript.

The FORZA TRIAL was funded by internal Academic Grants (Bando Linea D. 1105536). The authors also thank the Italian Ministry of Health for the funding within the “Ricerca corrente 2021” project.

A.M.L. received speaking honoraria from Abbott, Medtronic, Abiomed and from Bracco Imaging, F.B, C.T and C.A received speaker’s fees from Abbott, Medtronic, and Abiomed. G.Z., A.Z., D.G., F.D.G., F.B., R.V. and F.C have no conflicts of interest. Antonio Maria Leone is serving as one of the Editorial Board members of this journal. We declare that Antonio Maria Leone had no involvement in the peer review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to Manuel Martínez-Sellés, Grigorios Tsigkas, Athanasios Moulias and Anastasios Apostolos.