The future of interventional cardiology

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

Drug-coated balloon (DCB) is a therapeutic tool that has been available for the treatment of coronary artery disease for more than 20 years. Initially developed for in-stent restenosis,1,2 its use has expanded given its potential in native coronary lesions. In Spain, annual registry data show a marked increase in DCB utilization, from approximately 4% of percutaneous coronary interventions in 2012 to 15% in the most recent report,3 accompanied by a parallel decline in drug-eluting stent (DES) use. This growing adoption over the past few years has been driven largely by the “leave nothing behind” concept rather than by robust clinical evidence. Accordingly, American clinical practice guidelines do not recommend DCB over DES,4 and European clinical practice guidelines restrict their indication to in-stent restenosis.5 Nevertheless, DCB use has extended to increasingly complex clinical scenarios, including small vessels, diffuse disease, chronic total coronary occlusions, calcified lesions, acute coronary syndrome, patients at high bleeding risk, and bifurcation lesions.

In bifurcation lesions, 2 principal approaches have been described. The pure DCB technique involves treatment of both the main vessel and the side branch (SB) with DCB, and is limited to the SB in Medina 0,0,1 lesions. In contrast, the hybrid technique combines DES implantation in the main vessel with DCB dilation in the SB. Two variants of the hybrid approach exist: SB predilation with DCB before DES implantation in the main vessel, and SB postdilation with DCB after DES deployment in the main vessel through the stent struts. The former allows direct access to the SB with the DCB without compromising drug delivery but may be affected by carina shift following DES implantation, potentially requiring repeat dilation of the new segment treated with DCB. The latter carries the risk of DCB drug loss when crossing the stent struts, and the need to correct the deformation induced in the DES when dilating the SB.

The hybrid strategy has been evaluated in multiple observational studies for years. Its rationale lies in the ability of DCB to reduce late lumen loss through an antiproliferative effect in SB lesions, thereby decreasing restenosis, and the need for repeat revascularization, with a potential reduction in clinical events during follow-up. A reduction in late lumen loss at the SB ostium has indeed been demonstrated in most studies.6-9 However, the translation of this favorable effect into fewer clinical events is more difficult, with most studies reporting neutral results. The randomized DCB-BIF study, which had sufficient statistical power, compared the hybrid strategy with the provisional stenting technique.10 Although a significant reduction in events during follow-up was demonstrated, this was driven by myocardial infarction (periprocedural and spontaneous) and not by the need for repeat target lesion revascularization. After excluding periprocedural myocardial infarctions, no significant differences in major adverse events were observed at 1 year (5.1% vs 2.6%; P = .09). Although the study concludes that there is a significant reduction of events in the DCB-treated group, the higher incidence rate of periprocedural myocardial infarction in the control group (counted as an event) complicates the interpretation of the results. Although meta-analyses in this field provide another form of evidence, they are strongly influenced by the weight of this study. Thus, although most conclude that the hybrid strategy reduces events compared with the provisional stenting technique,11-13 these meta-analyses present the same interpretative limitations as the DCB-BIF study.

Regarding the use of the pure DCB strategy, there is still no evidence available, and we will have to wait for the results of the EBC-DCB study [NCT06822322], which is still in the patient inclusion phase.

In a recent article published in REC: Interventional Cardiology, Valencia et al. reported a nonrandomized comparison of patients with left anterior descending/diagonal artery bifurcations treated with the hybrid strategy and a DCB in the SB (n = 86) compared with patients treated with the provisional stenting technique (n = 88), with a mean follow-up of 3 years.14 The study concludes that the strategy of DES in the left anterior descending coronary artery and DCB in the diagonal branch reduced clinical events at the 3-year follow-up compared with the provisional DES strategy.

This study is timely, given the ongoing controversy in this field. However, several limitations warrant consideration beyond those already discussed. The use of the proximal optimization technique was notably low, particularly in the control group (only 12%). With the exception of Medina 0,0,1 bifurcations, this maneuver is recommended and generally considered mandatory in current consensus documents from the European Bifurcation Club.15 The presence of significant differences between the 2 groups penalizes the control group. Another noteworthy finding is the absence of myocardial infarction and target lesion revascularization in the DCB group over a 3-year period. Given the prolonged enrollment period (approximately 6 years), incomplete data capture at the time of analysis cannot be excluded, and some events may have been underreported.

Overall, this study provides relevant insights into a highly topical and debated issue, and the authors should be acknowledged for their effort in comprehensive data collection and long follow-up. Although the impact of DCB on clinical event reduction remains controversial, these findings support the potential clinical utility of this therapeutic strategy in the management of bifurcation lesions.

FUNDING

None declared.

CONFLICTS OF INTEREST

M. Pan declares having received minor payments for lectures from Abbott and Boston Scientific.

REFERENCES

Paclitaxel-coated balloons (PCB) have long dominated the drug-coated balloon (DCB) landscape, supported by favourable pharmacokinetics and extensive randomised evidence.1 Sirolimus, by contrast, is inherently less lipophilic and biologically dependent on sustained arterial wall exposure, rendering simple balloon-coating strategies suboptimal. Consequently, early-generation sirolimus- coated balloons (SCB) were met with skepticism regarding effective drug transfer and durable tissue retention. Signals of attenuated late lumen gain with SCB in early randomised comparisons, including the TRANSFORM I, highlighted these limitations.2 However, subsequent randomised trials in both de novo lesions and in-stent restenosis have failed to demonstrate a meaningful difference in late lumen loss versus PCB.3 Crucially, in contemporary meta-analyses, even when modest angiographic differences are observed, these have not translated into significant differences in clinically relevant outcomes, including target lesion failure, repeat revascularisation, or myocardial infarction.4,5

The SELUTION SLR platform (Cordis, United States) is a deliberate evolution in this field, incorporating a proprietary phospholipid carrier and micro-reservoir architecture designed to enable controlled and prolonged sirolimus release with minimal drug loss.6 The key question is whether this technological maturation translates into meaningful therapeutic equivalence.

In a recent paper published in REC: Interventional Cardiology, Faria et al. present a prospective single-center registry of 257 patients with 316 de novo lesions and provide a contemporary head-to-head comparison between the SELUTION SLR and the established Pantera Lux (Biotronik, Germany) PCB.7 The authors are to be congratulated for assembling a real-world cohort that included both acute and chronic coronary syndromes, a high prevalence of bifurcation disease, and frequent hybrid strategies. At 12 months, clinical outcomes were reassuringly low and statistically similar between devices, with a MACE rate of 5.8% and a target lesion failure rate of 3.8% overall. Target lesion revascularisation occurred in fewer than 1% of lesions.

Several aspects of the study merit recognition. The registry was prospective with complete 1-year follow-up. The investigators appropriately avoided multivariable or propensity modelling in the setting of low event counts, thereby avoiding the risk of statistical overreach. Lesion preparation was systematic, imaging use was encouraged, and bailout criteria was clearly defined, reflecting thoughtful procedural strategy.

Nevertheless, these findings do require careful interpretation. The treated population was predominantly small-vessel disease, with a mean DCB diameter of 2.25 mm and only 18.7% of vessels ≥ 3.0 mm. As such, these findings primarily reinforce the established role of DCB in small-calibre arteries rather than expanding indications into larger vessels. Although subgroup analysis in larger vessels did not reveal excess adverse events, bailout stenting was notably higher in ≥ 3 mm arteries (18.6%), suggesting that operator thresholds for permanent scaffolding may differ by vessel calibre. The observed reduction in mild, non–flow-limiting dissections with the SELUTION SLR (6.7% vs 14.7%) warrants careful interpretation. Types A-B dissections are expected following DCB angioplasty and are typically benign when TIMI 3 flow is preserved.8,9 Whether this difference reflects intrinsic coating behaviour, mechanical interaction, lesion preparation variability, or simply procedural nuance cannot be determined in the absence of randomisation or imaging adjudication. Similarly, the absence of no-reflow events in the SCB arm compared with 2.7% in the PCB group is hypothesis-generating but numerically small. The small number of events precludes definitive mechanistic interpretation.

Taken together, what conclusion can be reasonably drawn from these data? This study demonstrates that the SELUTION SLR platform is safe and clinically comparable to an established PCB in a predominantly small-vessel, real-world population. It does not demonstrate superiority in clinical endpoints. The procedural signals—fewer mild dissections and less no-reflow—are intriguing but remain angiographic observations rather than outcome-altering findings.

In this context, the evolution of sustained-release technology appears incremental rather than revolutionary. Importantly, these findings sit alongside a growing body of randomised evidence. In SELUTION DeNovo RCT, a sirolimus-eluting balloon strategy demonstrated non-inferiority to contemporary drug-eluting stents in selected de novo lesions, supporting the feasibility of a “leave-nothing-behind” approach.10 Whether such platforms will ultimately displace paclitaxel balloons or simply broaden therapeutic choice, remains to be determined by longer-term and adequately powered comparative trials.

For now, the balance has not decisively shifted—but the field is more competitive.

FUNDING

No external funding was received for this paper.

CONFLICTS OF INTEREST

R. Natarajan and K. Chandrasekharan have no conflict of interests and have received no funding related to this study. S.C. Eccleshall received speaker fees and acts as a consultant for B. Braun, Medtronic, Cordis and MedAlliance, and received grants for investigator- initiated research from B. Braun.

REFERENCES