Access to side branches with a sharply angulated origin: usefulness of a specific wire for chronic occlusions

INTRODUCTION

Percutaneous coronary intervention (PCI) is the first-line therapy in patients with ST-segment-elevation myocardial infarction (STEMI).1 The STEMI-related culprit vessel is usually considered as one of the most important prognostic factors in STEMI patients.2,3 This assumption comes from previous studies –conducted in the pre-reperfusion or thrombolysis era– which showed that left anterior descending artery (LAD)-related STEMIs were associated with worse clinical outcomes compared with right coronary (RCA) and left circumflex artery (LCX)-related lesions.4-9

However, in the contemporary era of primary PCI there are limited data about the prognostic impact of LAD as the STEMI-related culprit vessel especially in a very long follow-up.10,11

Therefore, the aim of this study was to investigate the impact of the LAD as the STEMI-related culprit vessel on very long-term clinical outcomes in STEMI patients undergoing primary PCI enrolled in the EXAMINATION-EXTEND study (10-year follow-up of the EXAMINATION trial).

METHODS

Study design and patients

The EXAMINATION trial (NCT00828087) was an all-comer, multicenter, prospective, 1:1 randomized, 2-arm, single-blind, controlled trial conducted at 12 centers across 3 countries to assess the superiority of EES (Xience V) vs BMS (Multilink Vision, Abbott Vascular) in STEMI patients regarding the primary endpoint of all-cause mortality, any myocardial infarction, and any revascularization at 1 year. The study had broad inclusion criteria and few exclusion criteria to ensure an all-comer STEMI population representative of the routine clinical practice. The study outcomes have been reported up to the year 5.12,13 After that, it was reinitiated as the EXAMINATION- EXTEND study to evaluate patient- and device-oriented composite endpoints at 10 years. The latter is registered at ClinicalTrials.gov (NCT04462315) as an investigator-driven extension of follow-up of the EXAMINATION trial. An independent study monitor (ADKNOMA, Barcelona, Spain) verified the adequacy of the extended follow-up and events reported. All events were adjudicated and classified by an independent event adjudication committee blinded to the therapy groups (Barcicore Lab, Barcelona, Spain). The 10-year primary endpoint results of the EXAMINATION-EXTEND study have been previously published.14 For the aim of this study, baseline, procedural characteristics and outcomes were stratified according to the STEMI-related culprit vessel (LAD vs others). All centers participating in the EXAMINATION trial received the approval of their Medical Ethics Committee, and all enrolled patients who had already signed their written informed consent forms. Medical ethics committee approval for EXAMINATION- EXTEND was granted at the institutions of the principal investigators (Hospital Clínic and Hospital Bellvitge, Barcelona, Spain), and the requirement to obtain informed consent to gather information on 10- year events was waived. The study complied with the Declaration of Helsinki.

Study endpoints

The primary endpoint of this study was the patient-oriented composite endpoint of all-cause mortality, any myocardial infarction, or any revascularization at 10 years. Secondary endpoints were each individual components of the primary endpoint, device-oriented composite endpoint (cardiac death, target-vessel myocardial infarction, target lesion revascularization), its individual components and stent thrombosis. Detailed descriptions of the study endpoints and definitions have been published previously.15

Statistical analysis

Continuous variables are expressed as median (interquartile range; IQR), and categorical variables as absolute and relative frequencies (percentages).

Baseline clinical, angiographic, and procedural characteristics were compared between the groups stratified by the STEMI-related artery (LAD vs other vessels) using the Wilcoxon rank sum test, the chi-square, or Fisher’s exact test, where appropriate.

Time-to-event curves for POCE and all-cause death were plotted using the one minus the Kaplan-Meier estimate and the cumulative incidence function for other outcomes. The incidence of events at the follow-up was compared between groups using log-rank or Grey’s test. Landmark analyses were also performed, setting landmark points at 1 and 5 years.

The association between LAD as a STEMI-related culprit vessel and events was analyzed in univariable and multivariable cause-specific Cox regression models. Covariates were added to the multivariable model in 2 blocks. The first model included all clinically relevant baseline characteristics variables with P < .1 in the between-groups comparison (LAD vs other vessels), i.e., sex, smoking status, peripheral vascular disease, previous PCI, previous CABG, previous MI, and Killip class. The second model (expanded adjustment) included both the baseline characteristics and the left ventricular ejection fraction (LVEF) at discharge.

Two-tailed P-value < .05 was considered statistically significant. All statistical analyses were performed using R (R Core Team (2022). R: a language for statistical computing. R Foundation for Statistical Computing, Austria) with the following packages: survival, tidycmprsk, jskm, and gtsummary.

RESULTS

Patient characteristics

In 631 (42%) out of the 1498 STEMI patients included in the EXAMINATION EXTEND trial, the LAD was the culprit vessel (LAD-STEMI group), whereas in 867 patients (58%) it was not (non- LAD-STEMI group). Patients’ inclusion flowchart is shown in figure 1.

Figure 1. Study flowchart. A total of 1498 patients were initially recruited. At 10 years, clinical follow-up was obtained in 95.2% of the patients. LAD, left anterior descending artery; STEMI, ST-elevation myocardial infarction.

LAD-STEMI group had a higher incidence of active smokers, advanced Killip class and more depressed LVEF vs the non-LAD-STEMI group, which, however, exhibited a higher incidence of peripheral vascular disease, previous MI and previous PCI (table 1). Also, although non-statistically significant, the frequency of late comers and bailout PCI was numerically higher in the LAD-STEMI group.

Table 1. Baseline clinical characteristics

Clinical characteristics	Overall (N = 1498)a	LAD-STEMI (N = 631)a	Non-LAD-STEMI (N = 867)a	Pb
Age (years)	61 [51-71]	61 [51-71]	61 [51-70]	.778
Sex (male)	1,244 (83%)	512 (81%)	732 (84%)	.094
Current smoker	415 (28%)	197 (31%)	218 (25%)	.009
Hyperlipidemia	655 (44%)	268 (43%)	387 (45%)	.419
Hypertension	725 (48%)	307 (49%)	418 (48%)	.843
Peripheral vascular disease	55 (3.7%)	14 (2.2%)	41 (4.7%)	.011
Previous stroke	31 (2.1%)	14 (2.2%)	17 (2.0%)	.726
Previous myocardial infarction	80 (5.3%)	23 (3.7%)	57 (6.6%)	.013
Previous PCI	61 (4.1%)	18 (2.9%)	43 (5.0%)	.042
Previous CABG	10 (0.7%)	1 (0.2%)	9 (1.0%)	.052
Clinical presentation				.126
PCI (< 12 h)	1,268 (85%)	520 (82%)	748 (86%)
Bailout PCI	98 (6.5%)	51 (8.1%)	47 (5.4%)
PCI after successful thrombolysis	34 (2.3%)	14 (2.2%)	20 (2.3%)
Late comer (> 12 h and < 48 h)	97 (6.5%)	46 (7.3%)	51 (5.9%)
Killip class				< .001
I	1,337 (90%)	525 (83%)	812 (94%)
II	115 (7.7%)	76 (12%)	39 (4.5%)
III	23 (1.5%)	20 (3.2%)	3 (0.3%)
IV	18 (1.2%)	8 (1.3%)	10 (1.2%)
In-hospital LVEF (%)	52 (45, 58)	46 [40-55]	55 [50-60]	< .001
Symptom onset to first medical contact time (hours)	1.38 (0.70, 3.00)	1.27 [0.67-3.00]	1.47 [0.75-3.00]	.353
CABG, coronary artery bypass graft; LVEF, left ventricular ejection fraction; PCI, percutaneous coronary intervention. a>Median [interquartile range] or frequency (%). bWilcoxon rank sum test; Pearson’s chi-squared test; Fisher’s exact test.

Regarding procedural data, LAD-STEMI group received smaller stent diameter (3.12 mm vs 3.26 mm; P = .001) and had a lower incidence of ST-segment resolution than the non-LAD-STEMI group (73%, vs 50%; P = .001) (table 2). The use of GP IIb/IIIa inhibitors was numerically lower in the LAD-STEMI group, although the differences between groups were not statistically significant. Of note, almost half of the patients (46%) with LAD-STEMI had the lesion in the proximal LAD compared with 44% of them who had it in the mid/distal LAD.

Table 2. Angiographic and procedural characteristics

Procedural characteristics	Overall (N = 1498)a	LAD-related STEMI (N = 631)a	Non-LAD-related STEMI (N = 867)a	Pb
STEMI-related culprit vessel				N/A
LAD	631 (42)	631 (100)	0 (0)
LMCA	3 (0.2)	0 (0)	3 (0.3)
RCA	650 (43)	0 (0)	650 (75)
LCx	207 (14)	0 (0)	207 (24)
SVG	7 (0.5)	0 (0)	7 (0.8)
Multivessel disease	188 (13)	72 (11)	116 (13)	.256
Total ischemic time (hours)	3.9 [2.7-6.8]	4.0 [2.7-7.3]	3.9 [2.7-6.3]	.366
Manual thrombectomy	976 (65)	405 (64)	571 (66)	.502
Glycoprotein IIb/IIIa inhibitor	785 (52)	312 (49)	473 (55)	.051
Direct stenting	885 (60)	390 (63)	495 (59)	.113
Stent type				.312
DES	751 (50)	326 (52)	425 (49)
BMS	747 (50)	305 (48)	442 (51)
No. of stents	1.39 (0.65)	1.37 (0.63)	1.40 (0.66)	.428
Total stent length (mm)	23 (18-35)	23 (18-33)	23 (18-35)	.154
Maximal stent diameter (mm)	3.20 (0.45)	3.12 (0.40)	3.26 (0.47)	< .001
Post-dilatation	221 (15)	97 (15)	124 (14)	.564
TIMI flow after PCI				.607
0	26 (1.7)	9 (1.4)	17 (2.0)
1	12 (0.8)	5 (0.8)	7 (0.8)
2	59 (4.0)	29 (4.6)	30 (3.5)
3	1396 (94)	584 (93)	812 (94)
ST-segment resolution > 70%	852 (63)	285 (50)	567 (73)	< .001
BMS, bare metal stent; CABG, coronary artery bypass graft. DES, drug-eluting stent; LAD, left anterior descending coronary artery, LCx, left circumflex artery; LMCA, left main coronary artery; PCI, percutaneous coronary intervention; RCA, right coronary artery; STEMI: ST-segment elevation myocardial infarction; SVG, saphenous venous graft; TIMI, thrombolysis in myocardial infarction. aMedian [interquartile range], mean (standard deviation) or frequency (%). bFisher’s exact test; Pearson’s chi-squared test; Wilcoxon rank sum test.

Ten-year outcomes

At the 10-year follow-up, POCE did not differ between LAD-STEMI and non-LAD-STEMI group (adjusted HR, 0.95; 95%CI, 0.79-1.13; P = .56) (figure 2). Moreover, no differences were found in terms of each individual component of POCE (all-cause mortality, MI, any revascularization) (figure 3) and other secondary endpoints (figure 1 of the supplementary data). Furthermore, when the expanded adjustment was performed and LVEF was included in the multivariable analysis, there were no inter-group differences between (table 3).

Figure 2. Central illustration. Outcomes of patients with ST-segment elevation myocardial infarction according to the culprit vessel at the 10-year follow-up. LAD, left anterior descending coronary artery; STEMI: ST-segment elevation myocardial infarction; POCE: patient-oriented composite endpoint.

Figure 3. Time-to-event curves for the patient-oriented composite endpoint (A), all-cause mortality (B), myocardial infarction (C), and any revascularization (D) in patients stratified according to the culprit vessel. LAD, left anterior descending coronary artery; MI, myocardial infarction; STEMI, ST-segment elevation myocardial infarction; POCE, patient-oriented composite endpoint.

Table 3. Ten-year outcomes

10-year outcomes	LAD-related STEMI (N = 631)	Non-LAD-related STEMI (N = 867)	Unadjusted HR (95%CI)	P	Adjusted HR (95%CI)	Pa	Expanded adjusted HR (95%CI)	Pb
Patient-oriented composite endpointc	220 (34.9)	307 (35.4)	0.99 (0.83-1.17)	.87	0.95 (0.79-1.13)	.56	0.98 (0.78-1.23)	.86
All-cause mortalityd	131 (21.6)	179 (21.2)	1.02 (0.82-1.28)	.84	0.93 (0.74-1.18)	.56	0.81 (0.59-1.09)	.17
Any myocardial infarctione	33 (5.5)	53 (6.3)	0.86 (0.56-1.33)	.50	0.93 (0.60-1.45)	.76	1.14 (0.67-1.93)	.61
Any revascularization	108 (17.4)	161 (18.8)	0.93 (0.73-1.18)	.55	0.96 (0.75-1.22)	.72	1.12 (0.83-1.52)	.45
Device-oriented composite endpointf	94 (14.3)	132 (14.2)	0.98 (0.75-1.28)	.88	0.91 (0.70-1.20)	.50	0.95 (0.67-1.35)	.77
Cardiac death	72 (9.8)	95 (10.0)	1.06 (0.78- 1.44)	.71	0.89 (0.65- 1.23)	.49	0.71 (0.47-1.09)	.12
Target vessel myocardial infarction	16 (2.6)	36 (4.2)	0.62 (0.34-1.11)	.10	0.69 (0.38-1.25)	.22	0.87 (0.43-1.77)	.71
Target lesion revascularization	44 (7.0)	63 (7.3)	0.97 (0.66-1.43)	.89	1.01 (0.68-1.49)	.96	1.20 (0.76-1.93)	.43
Definite/probable stent thrombosisg	17 (2.7)	28 (3.3)	0.84 (0.46-1.54)	.57	0.83 (0.45-1.55)	.57	0.80 (0.38-1.73)	.58
95%CI, 95% confidence interval; HR, hazard ratio; LAD, left anterior descending artery, STEMI: ST-elevation myocardial infarction. Data are expressed as no. (%). aCause-specific Cox regression model adjusted for sex, smoking status, peripheral vascular disease, previous percutaneous coronary intervention, previous coronary artery bypass graft, previous myocardial infarction, and Killip class. bCause-specific Cox regression expanded model, adjusted for baseline comorbidities and left ventricular ejection fraction at discharge. cComposite endpoint of all-cause death, any recurrent myocardial infarction, and any revascularization. dDeath was adjudicated according to the Academic Research Consortium definition. eMyocardial infarction was adjudicated according to the World Health Organization extended definition. fComposite endpoint of cardiac death, target vessel myocardial infarction, target lesion revascularization, and stent thrombosis. gStent thrombosis was defined according to the Academic Research Consortium definition.

Landmark analyses

POCE landmark analysis showed no differences between the 2 groups across different time points. (figure 4A). Looking specifically at the various POCE individual components, the LAD-STEMI group exhibited a higher rate of all-cause mortality within the first year vs the non-LAD-STEMI group (p = 0.041), but this difference disappeared thereafter (figure 4B). Between years 0 and 1, there was also a trend toward a lower rate of myocardial infarction in the LAD-STEMI group vs the non-LAD-STEMI group (p = 0.081), which disappeared after year 1 (figure 4C). No differences were ever found regarding any revascularization (figure 4D) or other secondary endpoints between the 2 groups (figure 2 of the supplementary data).

Figure 4. Landmark analysis for the patient-oriented composite endpoint (A), all-cause mortality (B), myocardial infarction (C), and any revascularization (D) in patients stratified according to the culprit vessel. LAD, left anterior descending coronary artery; MI, myocardial infarction; STEMI, ST-segment elevation myocardial infarction; POCE, patient-oriented composite endpoint.

DISCUSSION

The main findings of this study can be summarized as follows: a) STEMI patients with LAD as the culprit vessel have a different baseline clinical profile vs STEMI patients with other culprit vessels; b) in the contemporary era of primary PCI, LAD as the STEMI-related culprit vessel did not bring worse very long-term outcomes compared with other coronary vessels; c) nevertheless, between years 0 and 1 the LAD-STEMI group exhibited a higher all-cause mortality rate, which disappeared thereafter compared with non-LAD-STEMI group.

Cardiology community knows (as reflected by the ESC guidelines on the management of acute coronary syndromes) that STEMI with LAD involvement as culprit vessel is a clinical marker of high risk of further events.1 LAD-related STEMI represents, approximately, 40% up to 50% of all STEMIs,12,16 and its worse prognosis has been related to the large myocardium covered by the LAD flow compared with the myocardium supplied by other coronary vessels. Of note, those studies were performed in the pre-reperfusion4-7 and early thrombolysis/PCI era,8,9 when PCIs were still not widely available. In the PCI era, there are very few studies (with short or mid-term follow-ups ranging from 1 to 3 years) reporting that LAD-STEMI is associated with an increased risk of stroke, heart failure, all-cause mortality10,17 and cardiovascular death11 after the PCI.

In our analysis, conducted in a cohort where the PCI was extensively performed, LAD as the STEMI culprit vessel did not appear to confer a worse prognosis to patients at the 1- or even 10-year follow-up. Of interest, LAD-STEMI patients exhibited the classical clinical features related to LAD, such as advanced Killip class at the time of presentation, lower ST-segment resolution and lower LVEF, which is similar to previous studies.8-11,17 All these unfavorable clinical characteristics are indeed related to the large amount of myocardium damaged in a LAD-STEMI with subsequent heart failure and ventricular arrhythmias.17-19 Nevertheless, this did not translate into a worse, very long-term clinical outcome. Significantly, even after accounting for variations in LVEF (which we addressed separately in our model due to its perceived role in the outcome cascade) the results showed no differences. This observation stands in contrast to earlier evidence, where the higher mortality rate in this cohort had been partially attributed to the subsequent decline in LVEF after STEMI.9,10

Several explanations may be claimed to understand our main finding. It may be hypothesized that worse outcome related to anterior STEMI may have been overcome by the introduction of the PCI with quick myocardial reperfusion. Pharmacological treatment has been also improved from thrombolysis to the PCI era, not only in terms of antiplatelet agents, but also in terms of secondary prevention (high intensity statins and angiotensin converting enzyme inhibitors/angiotensin receptor blockers or angiotensin receptor/neprilysin inhibitors for left ventricular dysfunction).20-23 Furthermore, in our study, the LAD-STEMI group had a higher proportion of active smokers. Smoking cessation remains the most critical preventive measure for coronary artery disease. The relationship between smoking and cardiovascular outcomes has been a matter of discussion, as some studies have suggested improved cardiovascular outcomes, even in the long term, among smokers who experienced STEMI.24 However, many of these studies were observational registries conducted in the pre-PCI era. Recent evidence indicates that smoking is associated with more post-PCI long-term adverse outcomes.25 Therefore, the so-called “smoker’s paradox” might be better explained by factors such as younger age and a lower prevalence of other risk factors among smokers. Indeed, in our study, while the LAD-STEMI group had a higher proportion of smokers, they had a lower prevalence of other risk factors, such as peripheral vascular disease and a history of prior PCI or MI.

Last, but not least, in landmark analysis we found that between years 0 and 1, all-cause mortality was more common in the LAD-STEMI group. Notably, in this period, there was a numerically higher number of cardiac deaths (although not statistically significant, P = .12), a similar finding to other existing evidence that found a higher relatively short-term mortality in the LAD-STEMI group within the first 30 days. In these studies, the elevated short-term mortality was associated with acute sequelae, such as heart failure and was also speculated to be connected to other lethal complications, such as ventricular arrhythmias, cardiogenic shock or mechanical complications.10,11 In our cohort, we found a trend towards a higher rate of reinfarction in the non-LAD-STEMI group (P = .081) that was largely unrelated to TLR, TVMI, or stent thrombosis. This observation contrasts with previous literature that reported a more common occurrence of reinfarction at the follow-up in patients with the SVG as the culprit vessel26 as well as the LAD,8 but not in LCx or the RCA.9-11

Our 10-year follow-up revealed similar clinical event rates between LAD-STEMI and non-LAD-STEMI group, indicating absence of long- term divergence. Previous studies showed a favorable post-acute phase prognosis for LAD-STEMI patients,10,11 which is consistent with our findings. In fact, non-cardiac factors seem to impact long-term mortality more than infarct location does.19 Thus, patients with STEMI should receive uniform management focused on secondary prevention strategies, regardless of the culprit vessel. Unfortunately, insufficient long-term data collection limits deeper insights into these outcomes (such as the presence of heart failure, optimal medical therapy, or other comorbidities).

Limitations

This study presents several limitations. First, this is a non-prespecified post-hoc analysis of the EXAMINATION-EXTEND study and therefore its conclusions must be considered only hypothesis generating. The association between infarction and outcomes may be driven by confounders which have not been recorded in the study. Then, several clinical and procedural characteristics were not available for the analysis, such as specified in-hospital or follow-up clinical data, like optimal medical treatment or compliance to medication at the follow-up.

CONCLUSIONS

In a contemporary cohort of STEMI patients, there were no differences in POCE between LAD as the STEMI-related culprit vessel and other vessels at the 10-year follow-up. However, within the first year after STEMI, all-cause death was more common in the LAD-STEMI group. Our results should be considered as hypothesis-generating. Further studies are needed to specifically assess the relationship between infarction location and outcomes in a contemporary setting where interventional and medical treatments are optimized.

FUNDING

The EXAMINATION-EXTEND study was funded by an unrestricted grant of Abbott Vascular to the Spanish Society of Cardiology (promoter). P. Vidal Calés has been supported by a research grant provided by Hospital Clínic at Barcelona, Spain.

ETHICAL CONSIDERATIONS

The study fully complied with the Declaration of Helsinki and was approved by our Institutional Review Committee. All patients signed a written informed consent form before being included in this study. The clinical ethics committee gave its approval for the analysis of the data collected. In this work, SAGER guidelines regarding sex and gender bias have been followed.

STATEMENT ON THE USE OF ARTIFICIAL INTELLIGENCE

No artificial intelligence tools were used during the preparation of this work.

AUTHORS’ CONTRIBUTIONS

The authors declare they meet the full criteria and requirements for authorship and have reviewed and agree with the content of the article. P. Vidal Calés, K. Bujak, R. Rinaldi, A. Salazar Rodríguez, S. Brugaletta and M. Sabaté contributed to conceptualization, design, data analysis and drafting of the manuscript. L. Ortega-Paz, J. Gómez-Lara, V. Jiménez-Diaz, M. Jiménez, P. Jiménez-Quevedo, R. Diletti, P. Bordes, G. Campo, A. Silvestro, J. Maristany, X. Flores, A. De Miguel-Castro, A. Íñiguez, A. Ielasi, M. Tespili, M. Lenzen, N. Gonzalo, M. Tebaldi, S. Biscaglia, R. Romaguera, J.A. Gómez-Hospital and P. W. Serruys reviewed and edited the manuscript.

CONFLICTS OF INTEREST

M. Sabaté declares he has received consulting fees from Abbott Vascular and iVascular outside the submitted work. R. Romaguera is associate editor of REC: Interventional Cardiology. The journal’s editorial procedure to ensure impartial handling of the manuscript has been followed. The rest of the authors declared no conflicts of interest whatsoever.

REFERENCES

INTRODUCTION

Currently, the number of percutaneous coronary interventions (PCI) involving moderate-to-severe calcified plaques is increasing due to a progressively aging population and extending procedural indications into more comorbid patients. The presence of such calcification is extremely relevant as it is strongly associated with worse outcomes, specially by means of stent underexpansion, a potent predictor of stent thrombosis or in-stent restenosis.1-3 Moreover, calcified plaques can make advancing the devices difficult and trigger stent deformation and entrapment, coronary artery dissection, or perforation.1,4-6. Currently, there is a growing interest in the assessment of plaque morphology and its modification prior to stent implantation, which has led to the development of multiple tools such as rotational atherectomy, lithotripsy, orbitational atherectomy, cutting balloons (CB) and scoring balloons (SB).7-11 The latter are easy to use and aim to create a controlled fracture of calcium deposits and plaque dilatation to facilitate stenting.12-14 However, despite their theoretical simplicity, these devices are bulky and stiff, making it difficult to cross the lesion at the first attempt, navigate the vessel, and recross the lesion once inflated. Therefore, there is a need for a more trackable and better-profiled SB to improve the uptake of these devices to treat calcified coronary artery disease.

The newly designed Naviscore SB (iVascular, Spain) seeks to address these drawbacks. Its structure is based on 125-µm thick nitinol laser cut filaments arranged in an axial pattern placed over a semi-compliant high-pressure balloon with a nominal pressure of 8 atm, a rated burst pressure of 20 atm, and a mean burst pressure of 26 atm (figure 1). A nylon compensation tube in the shaft helps to re-wrap during balloon deflation. The mechanical properties of nitinol tend to regain its original shape once the balloon has been deflated. The nylon compensation tube elongates once the balloon has been inflated and due to its elastic properties, it regains its original length when deflated (video 1 of the supplementary data). The 2 mechanisms produce a powerful re-wrapping of the entire system when the balloon has been deflated, regaining its original crossing profile, which allows for easy lesion recross and further dilatations as many times as required. Axial distribution of scoring elements provides a high push against calcified lesions. Nitinol elastic properties provide a better navigability through tortuous calcific vessels compared with rigid scoring elements, such as stainless steel. The durable hydrophilic coating of the Hydrax Plus catheter (iVascular, Spain) significantly reduces its coefficient of friction to 0.04 by increasing slip and navigability. Also, its axial design enables a far larger contact area with the vessel wall compared with other devices with spiral configuration of nitinol filaments such as the AngioSculpt catheter (Philips Healthcare, The Netherlands) (figure 2). In vitro testing (iVascular, Spain) was conducted to measure the crossing profile of different SBs using a non-contact laser meter where the profile is calculated through the shadow that has been created. This allows us to measure the profile without exerting any pressure on the device.15 The Naviscore crossing profile is 5% lower than Angiosculpt, and 31% lower than Wolverine (Boston Scientific, United States). This catheter is available in a wide range of measures from 1.5 mm up to 3.5 mm in diameter and from 6.0 mm up to 15 mm in length, all of them compatible with a 6-Fr guiding catheter.

Figure 1. Structure of the Naviscore SB. MBP, mean burst pressure; RBP, rated burst pressure.

Figure 2. In vitro model assessment of the AngioSculpt scoring surface (upper image) vs the Naviscore (lower image). The Naviscore scoring surface is 6 times larger than that of the AngioSculpt.

The present study aims to demonstrate the safety and efficacy profile associated with crossing and treating calcified coronary lesions with the Naviscore SB.

METHODS

The Naviscore first-in-man study is a multicentric and prospective registry that evaluated the device safety and efficacy profile in the treatment of calcified lesions in 85 patients from 10 centers (9 in Spain and 1 in Portugal), all from the Euro 4C Group, founded in 2018 and focused on the cardiac care of calcified and complex patients. All operators involved in this study were experts in the treatment of calcified coronary lesions and familiar with most tools designed to treat such lesions.

Inclusion criteria were the presence of de novo moderate-to-severe calcified lesions by angiographic criteria in the native coronary tree of patients with chronic coronary syndrome scheduled for a PCI due to symptom persistence despite optimal medical therapy and/or evidence of inducible ischemia. The only exclusion criterion was the presence of the patient’s hemodynamic compromise.

The study was designed to assess the safety and efficacy profile of Naviscore in terms of delivery success when used as the first device to dilate the lesion, plaque modification capabilities, and complications. Consequently, operators were asked to use the Naviscore in all cases as the first device to cross and dilate the lesion. However, in cases of failed lesion crossing, dilatation with a small balloon was recommended with subsequent re-use of the same Naviscore catheter.

Operators involved in the study had little prior experience with the Naviscore in, at least, 3 cases and were asked to include, at least, 5 patients in the study. The operators assessed the performance of the catheter in each procedure in terms of pushability, navigability, crossing, deflation time, re-wrap, recrossing capabilities and ease of retrieval, and made a subjective comparison with their routinely used SB or CB.

The baseline clinical characteristics were recorded prior to the procedure and angiographical and optical coherence tomography (OCT) images were analyzed separately by 2 different operators. Coronary angiography was performed using, at least, 2 orthogonal projections to show stenosis as it is commonly used in the routine clinical practice. The view with the most severe stenosis was selected for the quantitative analysis of the lesion before and after the PCI. Lesion calcification was angiographically categorized as none/mild, moderate (radiopacities were only noted during the cardiac cycle movement prior to contrast injection) or severe (radiopacities noted without cardiac movement prior to contrast injection involving both sides of the arterial lumen).16 Lesions were categorized as A, B1, B2 and C based on the modified ACC/AHA Task Force classification, which is in turn, based on the morphology and potential complexity of the PCI.17 Procedural success was defined as an angiographically residual percent diameter stenosis < 30% after stent implantation, absence of major complications and final Thrombolysis in Myocardial Infarction (TIMI) grade-3 flow.18 OCT analysis was performed as recommended in the routine clinical practice: lesion and proximal and distal references within 5 mm were used to estimate diameters and areas. Calcium cracks were defined as fissures involving a calcified region.19,20

Statistical analysis

Data are expressed as mean ± standard deviation for continuous variables with a normal distribution, median and interquartile range [IQR] for continuous variables with a non-Gaussian distribution, and counts and percentages for categorical data.

Statistical analyses were performed using the Stata software version 16.1 (College Station, TX, United States).

Ethical considerations

Informed consent was obtained from all the patients and the study was approved by the Research Ethics Committee. The authors declare that procedures were followed according to the regulations established by the Clinical Research and Ethics Committee and the Declaration of Helsinki of the World Medical Association.

RESULTS

From November 2021 through February 2022, a total of 85 patients—80% males—with a mean age of 71 ± 11 years were included in the present study. One center included a total of 21 patients and the remaining 9, between 5 and 10 patients each. Baseline patient and lesion characteristics are shown in table 1. Regarding comorbidities, the prevalence of diabetes mellitus, dyslipidemia, hypertension, and chronic kidney disease was 44%, 70%, 75%, and 18% respectively. Prior revascularization was present in 43% of the patients (PCI in 38% and coronary artery bypass graft in 16%). The left anterior descending coronary artery was the most common location of target lesions (41%), followed by the right coronary artery (28%), left circumflex artery (16%) and left main coronary artery (15%). Most lesions (87%) were categorized as type B2/C, 66% were severely calcified and 34% had moderate calcification by angiographic assessment. Chronic total occlusion was reported in 10% of treated lesions. Reference vessel diameter was 3.0 ± 0.5 mm; mean lesion length, 20.3 ± 9.4 mm; and diameter stenosis, 81.4 ± 12%.

Table 1. Baseline clinical and angiographic characteristics

Clinical and angiographic characteristics (n = 85)	n (%)
Age, years	71 ± 11
Male	68 (80%)
Diabetes	37 (44%)
Dyslipidemia	59 (70%)
Hypertension	67 (75%)
Chronic kidney disease	15 (18%)
Current/former smokers	53 (62%)
Prior PCI/CABG	37 (43%)
Type B2/C lesions	74 (87%)
Severe calcification	56 (66%)
Moderate calcification	29 (34%)
Basal percent diameter stenosis	81 ± 12%
Chronic total occlusion	8 (10%)
Lesion location: Left main coronary artery	13 (15%)
LAD	35 (41%)
RCA	24 (28%)
LCx	13 (16%)
CABG, coronary artery bypass graft; LAD, left anterior descending coronary artery; LCx, left circumflex artery; PCI, percutaneous coronary intervention; RCA, right coronary artery.

The Naviscore catheter diameters used to dilate the lesions were 2.0 mm (21%), 2.5 mm (38%), 3.0 mm (31%), and 3.5 mm (10%). Mean number of device inflations was 2.7 ± 1.5 times.

The Naviscore crossing performance of is shown in figure 3. Despite the strong recommendation to use Naviscore as the first device, some operators decided to use Rotablator or small balloons first in 10 patients due to severely narrowed and/or calcified vessels. In all those cases, the Naviscore successfully crossed and dilated the lesion after the first attempt. In the 75 patients in whom the Naviscore was used as the first device, the lesions were crossed and treated successfully in 57 (76%) of them. In the remaining 18 (24%) patients, the Naviscore crossed the lesion after pre-dilatation with a small balloon in 16 (89%) patients. Only 2 patients had non-crossable lesions.

Figure 3. Crossing performance of the Naviscore.

PCI results and in-hospital outcomes are shown in table 2. Procedural success was achieved in 94% of cases. The mean lesion percent diameter stenosis decreased from 81.4 ± 12% at baseline to 33.3 ± 8.5% after Naviscore dilatation, with a residual percent diameter stenosis of 7.5 ± 2.6% after stent implantation. There were no in-hospital major adverse cardiovascular events or any cases of perioperative perforation or device entrapment. Coronary dissections occurred in 13% of the cases (all of them type A or B) and resolved after stent implantation.

Table 2. Angiographic and in-hospital results

Angiographic and in-hospital clinical results (n = 85)	n (%)
Procedural success: residual percent diameter stenosis < 30% after stenting, absence of major complications and TIMI grade-3 flow	80 (94%)
Percent diameter stenosis pre-Naviscore	81 ± 12%
Percent diameter stenosis post-Naviscore	33 ± 8.5%
Percent diameter stenosis post-stenting	7.5 ± 2.6%
MACE (in-hospital)	0%
Death, MI, emergency CABG	0%
Perforation	0%
Limiting flow dissection	0%
Type A or B dissection	11 (13%)
Device entrapment	0%
CABG, coronary artery bypass graft; MACE, major adverse cardiovascular events; MI, myocardial infarction; TIMI, Thrombolysis in Myocardial Infarction.

Ten procedures were OCT-guided. Pre-dilatation analysis could only be performed in 5 lesions; the OCT catheter could not cross the remaining lesions. Four of those had Fujino’s scores8 of 4 and in 2 of them the nodules protruded into the lumen. After dilatation, all lesions exhibited dissections that covered the intima and the media. Fractures were seen in all calcified plaques, which were deeper and wider in non-nodular calcified regions. Enlargement of lumen area after treatment with the Naviscore and correct stent apposition and expansion was observed in all imaging-guided cases (figure 4).

Figure 4. Clinical examples of 2 different lesions treated with the Naviscore. Angiography and baseline OCT (A) after dilatation with the Naviscore catheter (B) and post-stent implantation (C). On the left side, panel A shows a severely stenotic fibrocalcific plaque on the left anterior descending coronary artery that Naviscore (B) modifies creating calcium fractures (*) and dissection (arrow) resulting in stent implantation with good apposition and expansion (C). The right side shows a severely calcified plaque on the right coronary artery (A) with an arc of calcium of 180º at its proximal edge (lateral OCT picture) and 360º at its distal edge (central OCT picture) that the Naviscore modifies (B) creating calcium fractures (*) and dissection (arrow) resulting in stent implantation with good apposition and expansion (C). OCT, optical coherence tomography.

Table 3 shows the subjective performance of the Naviscore as evaluated by the operators of the present study. The Naviscore performance including push, navigability, crossing, deflation time, re-wrap, recrossing capabilities and ease of retrieval was deemed superior to the Wolverine, NSE Alpha (Nipro Co. Ltd., Japan), AngioSculpt, and Scoreflex (OrbusNeich, China).

Table 3. Subjective performance of the Naviscore compared with traditional and scoring or cutting balloons of participant centers. Push, capacity to cross the lesion, deflation time, rewrap and recrossing capabilities were the most valued characteristics of the Naviscore

Parameter	Push	Navigability	Crossing	Friction	Device visibility	Deflation time	Rewrap	Recrossing capability	Ease of retrieving	Global evaluation
Better	60%	54%	63%	52%	34%	65%	65%	69%	53%	78%
Equal	38%	46%	35%	46%	65%	34%	34%	29%	46%	21%
Worse	2%	0%	2%	2%	1%	1%	1%	2%	1%	1%

DISCUSSION

Findings of this first-in-man registry with the new SB Naviscore in moderately to severely calcified coronary lesions performed in CHIP (complex and high-risk intervention in indicated patients) by highly experienced operators on this field can be summarized as follows: a) the Naviscore was able to cross the lesions as the first device in 3 out of 4 patients in such difficult scenario; b) this device proved to be effective to treat complex coronary lesions, with procedural success rates of 94%; c) the Naviscore was safe as no major dissection, perforation, or device entrapment were observed and d) the performance of the Naviscore SB was better compared with other commercially available SB and CB as subjectively assessed by the experienced operators in this study.

Calcified coronary lesions account for up to 30% of lesions scheduled for PCI and are associated with worse clinical outcomes.1 Furthermore, these lesions are probably the most challenging ones for PCI operators. Thus, it is of paramount importance to develop specific devices for this scenario.21-23 Although several plaque-modification techniques have appeared in recent years, there are not very many head-to-head comparisons, thus complicating the choice between them. In contrast, several treatment combinations and algorithms have been published.24-27 Ablation techniques, such as rotational or orbital atherectomy, are especially indicated in uncrossable or undilatable lesions with balloon catheters. However, since there are more potential complications and a steeper learning curve associated with these therapies, developing new tools with a better crossing profile would be very positive in this scenario. The good crossability of the Naviscore SB showed in the present study is probably related to its unique nitinol structure in an axial configuration. CB such as the Wolverine or the NSE Alpha have a similar axial configuration of their cutting elements. However, the crossing profile of the Naviscore is 31% smaller than the CB. Although a comparative study on the crossing capabilities of those devices is not available, such a different profile favors the superior crossing capabilities of the Navis­core device. In fact, the operators of the present registry highlighted the ability to cross and recross lesions as one of the best features of the device compared with their usual CB or SB. Compared with the AngioSculpt—a SB that shares a nitinol structure with the Naviscore— the helical configuration of nitinol filaments in front of the axial alignment of the Naviscore nitinol filaments can make a difference. Axial alignment adds push to the device through the lesion, while the helical nitinol configuration can deform the structure under friction, thus reducing its navigability and, in some cases, cause device entrapment.28 Furthermore, as shown in figure 2, helical distribution of nitinol significantly reduces the nitinol scoring surface in front of an axial distribution.

The efficacy of the Naviscore balloon has proven to be good in the present study, with a procedural success rate of 94%. Furthermore, quantitative angiographic analysis showed a reduction of basal stenosis from 81% to 31% after Naviscore dilatation and to 7.5 ± 2.6% after stent implantation. Finally, the OCT evaluation confirmed the presence of extensive calcium fractures caused by the scoring filaments (figure 4). As the balloon gradually inflates, the radial forces concentrate along the surface of the nitinol scoring elements, resulting in a more controlled balloon expansion, increasing the force of the nitinol frame filaments to break down the calcified plaques.29 In vitro experiments comparing a simple SB (Scoreflex) with a conventional balloon catheter to dilate concentric tubes of calcium revealed that the inflation pressure required to break down the calcium tubes was consistently lower with SB. Finite element analysis revealed that the first main stress applied to the calcified plaque was, at least, 3-fold higher when inflating the balloon catheter with scoring elements.30 Naviscore has the largest scoring surface in the SB current market, being 6 times more extensive than the AngioSculpt (figure 2). Pressure concentration of the scoring elements is the mechanism of the increased ability of SB to dilate calcified lesions and facilitate stent expansion. Residual stenosis after stent placement was 7.5 ± 2.6% in our study.

Finally, the Naviscore proved to be safe in the present study, which could be justified by the mechanism of action of the device that uses nitinol filaments as the anchor to avoid balloon slippage, and allows balloon controlled expansion, minimizing the risk of barotrauma, coronary dissection, and perforation. Using OCT imaging, SB broke down the calcified lesion without the undesirable dissection of noncalcified segments, thus allowing successful stent implantation with adequate expansion.29,30

Limitations

One limitation of the study is its own design as a registry and therefore, the absence of a randomized comparator. Instead, expert operators in the treatment of calcified coronary lesions were asked to subjectively compare the device at test with their commonly used SB or CB in terms of push, cross/recross, rewrap, navigability and time of deflation. The subjective nature of this assessment, while providing valuable information, could be a limitation.

Another limitation is the sample size of the study, especially the size of the population involved in the OCT imaging analysis. Unfortunately, in our setting, the use of this technique to analyze calcified lesions, although on the rise, is still far from what would be recommended. However, and despite the limitations in terms of number, the cases analyzed with intracoronary imaging homogeneously show us the effect of the device under study—calcium fractures, dissection and increase in luminal area—as well as the optimal stent expansion.

The small sample of patients in this study does not allow for a disaggregated analysis by sex to draw any valid results.

CONCLUSIONS

The Naviscore SB is a step ahead in this field with an innovative design using a nitinol frame with axial distribution of filaments placed over a high-pressure balloon to improve current SB or CB designs. This provides a strong pushing capability and flexibility to cross the most difficult calcified lesions in 3 out of 4 patients and easily navigate through tortuous anatomy. Superior scoring surface provides strong plaque modification capabilities by facilitating calcium fractures and controlled dissections, and ultimately, optimal stent expansion. Uniform and controlled balloon expansion and the anchor effect provided by the nitinol frame minimizes the risk of uncontrolled dissections and distal embolization, thus providing an outstanding safety profile, confirmed in this study by the absence of major adverse cardiovascular events, device entrapment or flow- limiting dissections. Therefore, the Naviscore can be considered as the front-line SB, either alone or in combination with atheroablative techniques in the treatment of moderate-to-severe calcified lesions.

FUNDING

This study was partly funded by iVascular, Barcelona, Spain, who provided the devices to perform the study.

ETHICAL CONSIDERATIONS

Informed consent was obtained from all patients and the study was approved by the Research Ethics Committee. The authors declare that the procedures were followed in full compliance with the regulations set forth by the Clinical Research and Ethics Committee and Declaration of Helsinki of the World Medical Association. In accordance with the regulations of the SAGER guidelines, the small sample of patients in this study does not allow for a disaggregated analysis by sex to draw any valid results.

STATEMENT ON THE USE OF ARTIFICIAL INTELLIGENCE

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

AUTHORS’ CONTRIBUTIONS

A. Serra Peñaranda designed the protocol, database and study outline, participated in data collection, coordinated data analysis and interpretation, and drafted the article. E. Fernández Peregrina participated in data collection, data analysis and interpretation and drafted the article. M. Jiménez Kockar participated in data collection, data analysis and interpretation, and performed the statistical analysis. B. García del Blanco, S. Romani, J. Martín-Moreiras, E. Pinar Bermúdez, A. Rodrigues, S. Ojeda, N. Gonzalo López, A. Regueiro and A. Serrador Frutos participated in data collection and critically revised the manuscript. All authors gave their final approval to the last version for publication.

CONFLICTS OF INTEREST

S. Ojeda is an associate editor of REC: Interventional Cardiology. The journal’s editorial procedure to ensure impartial handling of the manuscript has been followed. A. Serra Peñaranda and Ander Regueiro received consulting fees from iVascular, Barcelona, Spain. The remaining authors declared no conflicts of interest whatsoever.

REFERENCES

INTRODUCTION

Percutaneous coronary intervention (PCI) has grown exponentially along with the technological evolution associated with this procedure. The continuous advancement of technology has enabled the development of stents with thinner struts, which offer a series of advantages over stents with thicker struts. One of the advantages of these new stents is the improved device profile—with increased flexibility—providing better navigability and greater lesion crossing capability. On the other hand, ultra-thin struts (UTS) cause fewer disturbances to normal laminar blood flow at target lesion level, due to the reduced protrusion of material into the vascular lumen. This seems to be associated with a lower degree of platelet activation and muscle cell proliferation,—the processes involved in stent failure—in terms of stent thrombosis (ST) and in-stent restenosis.1,2 In lesions located in small caliber vessels (≤ 2.5 mm), the use of UTS could provide additional advantages due to a higher ratio between the size of the struts and the lesion luminal area.3 Furthermore, UTS stents seem to be associated with less acute damage to the vascular endothelium during stent deployment. This reduced initial aggression could diminish the barotrauma-related inflammatory response and, therefore, prevent in-stent restenosis and promote faster device endothelialization.4,5 Studies have indicated that the use of UTS stents could be associated with lower rates of in-stent restenosis and a reduced need for new revascularizations.6,7

The Evermine 50 EES stent (Meril Life Sciences, India) is a UTS (50 μm) stent with CE marking consisting of a cobalt-chromium alloy platform with an everolimus-eluting biodegradable polymer. The aim of this study was to evaluate the 1-year safety and efficacy outcomes after UTS stent deployment in real-world patients with coronary artery disease.

METHODS

We conducted a prospective, non-randomized, multicenter study with patients who underwent UTS stent deployment at 4 different Spanish hospitals (data from the Everythin Registry). To be included in the study, patients had to be older than 18 years, with available coronary angiographies in the context of chronic or acute coronary syndrome, and have, at least, 1 target lesion with a 2 mm up to 4.5 mm reference vessel diameter on visual estimation. Overlapping stents was ill-advised and, if necessary, the overlap length should be ≤ 2 mm. PCI in multiple vessels and lesions during the same surgical act was allowed, and deferred procedures within the first 90 days since the initial procedure were also accepted. In these cases, any further procedures were not coded as an event—i.e. need for new revascularization—but as scheduled procedures. Only 1 case—1 target lesion treated with UTS stent deployment—was counted per patient. Deploying the study UTS stent was not mandatory in any of the other treated lesions, only in the target lesion/vessel.

The study followed the privacy policy of each research center, including regulations for the appropriate use of data from patient research. The study was approved by the Ethics Committee for Drug Research of the coordinating center. Moreover, the study was conducted in full compliance with the terms set forth in the Declaration of Helsinki. All patients signed specific informed consent forms prior to being included in the study.

Study device and procedure

The Evermine 50 EES (Meril Life Sciences, India) is a UTS (50 μm) stent with a cobalt-chromium platform coated with a biodegradable polymer composed of poly-L-lactic acid and poly(lactic-co-glycolic) acid. The Evermine stent—which has a hybrid design with an open cell in its central part and a closed cell at the edges—releases everolimus (1.25 μg/mm²) as the antiproliferative drug. The stent has received the corresponding CE marking and is available in several lengths from 8 mm up to 48 mm with diameters ranging from 2 mm up to 4.5 mm. The main features of the Evermine 50 EES device are illustrated in figure 1.

Figure 1. A: illustrative image of the Evermine 50 stent (Meril Life Sciences, India). B: description of the main characteristics of the stent. C: comparison of the study stent strut thickness vs major competing next-generation stents. PLGA, poly(lactic-co-glycolic acid); PLLA, poly-L-lactic acid (Images courtesy of Meril Life Sciences. Images reproduced with permission from Meril Life Sciences or its affiliates.)

PCI was performed following each center routine practice within the recommendations outlined in the clinical practice guidelines.8 The PSP algorithm (predilation, sizing [stent size selection], and postdilation) was recommended for optimal device implantation. The study protocol recommended postdilation, especially in cases where any degree of underexpansion was identified immediately after device implantation. Although the study protocol recommended the use of intravascular imaging modalities to guide the procedure, this was left to the operator’s discretion. All patients received a 300 mg loading dose of acetylsalicylic acid prior to the intervention followed by a loading dose of a second antiplatelet agent—clopidogrel, prasugrel, or ticagrelor—after the PCI, which was maintained for 3 up to 12 months and left to the discretion of the responsible investigator of the center.

Endpoints and definitions

The primary endpoint of the study was the occurrence of major adverse cardiovascular events (MACE) at 12 months. MACE were defined as the composite of cardiac death, non-fatal target vessel myocardial infarction (MI), or the need for target lesion revascularization. Secondary endpoints included each individual component of the composite endpoint, the overall mortality and ST (both definite and probable) according to the definitions of the Academic Research Consortium9 12 months after implantation. Additionally, the rates of device and procedural success were taken into consideration. Device success was defined as the deployment of the study stent in the target lesion with a final percent diameter residual stenosis < 30% by visual estimation. Procedural success was defined as the success of the device without any in-hospital complications, including death, MI, and target lesion revascularization.

Statistical analysis

Quantitative variables are expressed as mean and standard deviation or as median and interquartile range [IQR], depending on their distribution. Categorical variables are expressed as number and percentage. All analyses were performed using the statistical tool STATA 12 (StataCorp LLC, United States).

RESULTS

Demographic and baseline clinical characteristics

A total of 161 patients were included in the study from November 2020 through April 2022 whose demographic data and clinical characteristics are shown in table 1. The mean age was 64 ± 14 years, and 79% were male. A total of 66% of the patients were hypertensive; 53% had dyslipidemia; 34%, diabetes mellitus, and 59% a history of smoking. A total of 20% of the patients had experienced a prior MI, and 22% a previous PCI. The most common indication for the intervention was the diagnosis of non-ST-segment elevation acute myocardial infarction (42%), followed by ST-segment elevation myocardial infarction (STEMI) (22%) and chronic coronary syndrome (21%).

Table 1. Baseline characteristics of the study population

Basal characteristics	Patients (n = 161)
Age (years) ± SD	64 ± 14
Male, n (%)	126 (79)
BMI (kg/m²)	28 ± 3.5
Hypertension, n (%)	106 (66)
Dyslipidemia, n (%)	86 (53)
Diabetes mellitus, n (%)	55 (34)
Smoking status, n (%)
Non-smoker	65 (40)
Former smoker	49 (30)
Current smoker	47 (29)
Previous AMI, n (%)	33 (20)
Previous stroke, n (%)	2 (1.2)
Atrial fibrillation, n (%)	7 (4.3)
Peripheral vascular disease, n (%)	10 (6.2)
Previous coronary angioplasty, n (%)	36 (22)
Previous coronary artery bypass grafting, n (%)	4 (2.5)
COPD, n (%)	13 (8)
Chronic kidney disease, n (%)	14 (9)
Glomerular filtration rate (mL/min/1.73 m²)	61 ± 10
Left ventricular function, (%)	55 ± 11
Indication for coronary angiography, n (%)
Chronic coronary syndrome	34 (21)
Unstable angina	24 (15)
NSTEMI	67 (42)
STEMI	36 (22)
AMI, acute myocardial infarction; BMI, body mass index; COPD, chronic obstructive pulmonary disease; NSTEMI, non-ST-segment elevation acute myocardial infarction; SD, standard deviation; STEMI, ST-segment elevation myocardial infarction.

Angiographic and procedural characteristics

The lesion angiographic characteristics, and the results of the intervention are shown in table 2. Most patients had significant single-vessel disease (71%), being the presence of 2 or 3-vessel disease far less common (20% and 9%, respectively). The most widely treated vessel was the left anterior descending coronary artery (54%), followed by the right coronary artery (27%) and the left circumflex artery (17%). The target lesion median percent diameter stenosis by visual estimation was 90% [IQR, 75-99]. A total of 29% of the target lesions showed some degree of calcification on angiography. Intracoronary imaging modalities (7% optical coherence tomography) were used to guide the PCI in 11% of the cases. The mean number of stents deployed per lesion was 1.04 ± 0.22, with a median stent diameter of 3.0 mm [IQR 2.75-3.5] and a median stent length of 19 mm [IQR 19-24]. Pre- and postdilation were performed in 71% and 39% of the cases, respectively. The device and procedural success rates were 100%, without any procedure-related complications being reported in patients treated during the inpatient period.

Table 2. Angiographic, procedural and clinical follow-up characteristics of the cohort

Angiographic and procedural characteristics	Patients (n = 161)
Radial access, n (%)	158 (98)
Diseased vessels, n (%)
1-vessel disease	114 (71)
2-vessel disease	32 (20)
3-vessel disease	15 (9)
Target lesion location, n (%)
Left main coronary artery	3 (1.8)
Proximal left anterior descending coronary artery	37 (23)
Mid left anterior descending coronary artery	40 (24.8)
Distal left anterior descending coronary artery	10 (6.2)
Proximal left circumflex artery	10 (6.2)
Mid left circumflex artery	11 (6.8)
Distal left circumflex artery	6 (3.7)
Proximal right coronary artery	13 (8)
Mid right coronary artery	18 (11.2)
Distal right coronary artery	13 (8)
Bifurcation lesions, n (%)	12 (7.5)
Calcified lesions, n (%)	46 (29)
Visual percent diameter stenosis, median [IQR]	90 [75-99]
Predilation, n (%)	114 (71)
Postdilation, n (%)	63 (39)
Intracoronary imaging modalities, n (%)	18 (11)
Optical coherence tomography	11 (7)
Intravascular ultrasound	7 (4)
No. of stents deployed, mean ± SD	1.04 ± 0.22
Stent diameter (mm), median [IQR]	3.0 [2.75-3.5]
Stent length (mm), median [IQR]	19 [19-24]
Device success, n (%)	161 (100)
Procedural success, n (%)	161 (100)
Antiplatelet therapy after PCI, n (%)
Acetylsalicylic acid	161 (100)
Clopidogrel	78 (48)
Ticagrelor	68 (42)
Prasugrel	15 (9)
Clinical follow-up
12-month follow-up, n (%)	158 (98)
MACE, n (%)	4 (2.5)
Cardiac death	1 (0.6)
Target vessel MI	2 (1.3)
Target lesion revascularization	2 (1.3)
Overall mortality, n (%)	3 (1.9)
Stent thrombosis, n (%)
Definite	2 (1.3)
Probable	1 (0.6)
IQR, interquartile range; MACE, major adverse cardiovascular events; MI, myocardial infarction; PCI, percutaneous coronary intervention; SD, standard deviation.

Clinical outcomes at the follow-up

The 12-month follow-up was completed in 158 patients (98%). One year after implantation, 4 patients exhibited MACE (2.5%), and 3 patients died (1.9%). The cause of death was cardiac in 1 patient (due to a probable ST 7 days after the procedure) and non-cardiac in the remaining 2 (one due to lung neoplasm and the other to multiple organ failure). There were 2 non-fatal MIs (1.3%), both due to late definite ST (1 occurred 8 months after stent deployment and was associated with the study UTS stent, while the other one occurred 9 months after deployment due to a different thrombosed non-UTS stent implanted in a lesion of the target lesion same vessel. Only 2 patients required target lesion revascularization at the follow-up (1 due to ST and the other one due to in-stent restenosis).

DISCUSSION

The present study prospectively and multicentrically evaluates the safety and efficacy profile of implanting an UTS stent in a real-world population. Its main findings are that the UTS stent demonstrated a high procedural success rate, without in-hospital complications, acceptable midterm clinical outcomes, and a 2.5% rate of MACE 12 months after implantation.

The baseline characteristics of the study population are similar to the ones reported in previous studies that analyzed various stent technologies in patients with atherosclerotic coronary artery disease.10-12 However, it is noteworthy that in this study, 79% of cases were performed in the context of an acute coronary syndrome, including 22% of patients diagnosed with STEMI. In acute coronary syndrome—especially STEMI—there are factors associated with poorer outcomes of the implanted device, both in the short and long term. Firstly, the state of generalized vasoconstriction of the coronary tree and high thrombotic burden can complicate the appropriate selection of the size of the stent, thus leading to the implantation of smaller devices in relation to the actual size of the vessel, a mechanism involved in ST and in-stent restenosis. Furthermore, in the context of acute lesions, there is a higher risk of embolization and no-reflow or slow-flow phenomena, which can sometimes condition suboptimal final outcomes in terms of distal coronary flow, involving a greater risk of further ST. In our study, no ST occurred in patients with an early diagnosis of STEMI. Although it is worth mentioning that the results of the study stent were good—even in demanding contexts such as STEMI—the absolute number of STEMI patients included was low, meaning that data should be contrasted in larger series.

UTS stents provide better navigability, flexibility, and conformity to the vessel geometry. However, there may be doubts on whether the presence of UTS can lead to a reduction of the stent radial strength, which could have further implications for treating more unfavorable lesions, such as calcified lesions. Although, in the present study, 29% of the treated lesions showed some degree of calcification on angiography, the success rate of the stent reached 100%. This demonstrates the good performance of this UTS stent across different scenarios, achieving excellent radial strength even in the most challenging situations, such as calcified coronary lesions. These results are especially relevant in the specific context of the study, where, despite the recommendation for systematic postdilation, the final rate of stent postdilation was relatively low (39%).

Previous studies have consistently shown good clinical follow-up results for UTS stents with low rates of ST.13-15 The reason for this low rate of ST would be strut thickness per se, which would favor early neointimal coverage, thereby reducing the risk of ST (especially late and very ST).4 In the specific case of the study device (Evermine 50 EES), Patted et al.13 described the 6-month follow-up results of 251 patients. In this single-center, prospective experience, the authors describe a 6-month rate of MACE of 0.8%, with no ST at the follow-up. Regarding differences with respect to our series, nearly one-third of the cases were procedures in asymptomatic patients or with silent ischemia. Additionally, the rate of postdilation (57%) was higher than that of our cohort, which may have influenced the ST outcomes. The same group retrospectively described the results of 171 patients treated with the Evermine 50 EES stent,16 with 2-year rates of procedural success and MACE of 100% (same as in our study) and 2.4%, respectively. Again, the authors noted the absence of definite or probable ST at the follow-up. In this single-center cohort, the rate of stent postdilation was not reported, which may have implications for the prevention of MACE, especially ST. A meta-analysis that analyzed various types of UTS stents found no significant differences in the likelihood of stent failure, including ST across different stents with struts < 70 μm.17 In the present study, although the 1-year rate of definite ST after stent deployment was 1.3%, only 1 of these STs was attributed to the study device. The rate of ST is similar to that of other real-world experiences with second and third-generation stents,18-20 which confirms the good performance of the Evermine 50 EES in unselected real-world patients.

Limitations

The main limitations of the study are the relatively low number of patients included, and the absence of a comparator group. Furthermore, although the events reported at the follow-up were reviewed by the principal investigator of the coordinating center based on the case reports submitted by each principal investigator from the collaborating centers, these events were not allocated by an independent event adjudication committee. The fact that, in our cohort, few intracoronary imaging modalities were used to guide the PCI—reflecting real clinical practice—could be interpreted as a limitation of the study.

CONCLUSIONS

With data from a prospective, multicentric study of real-world patients, the PCIs performed with a 50 μm UTS stent, with a biodegradable polymer and everolimus elution had good clinical outcomes and a favorable safety profile at the 12-month follow-up.

FUNDING

None declared.

ETHICAL CONSIDERATIONS

The study was approved by the Drug Research Ethics Committee of the coordinating center. The study was conducted in full compliance with the terms outlined in the Declaration of Helsinki. All patients signed specific informed consent forms prior to the intervention and before being included in the study.

STATEMENT ON THE USE OF ARTIFICIAL INTELLIGENCE

No artificial intelligence was used for this work.

AUTHORS’ CONTRIBUTIONS

J. Casanova-Sandoval and M. García-Guimarães participated in the conception and design of the study, analysis and interpretation of results, and drafting the manuscript. G. Miñana Escrivà, E. Bosch-Peligero, J.F. Muñoz-Camacho, D. Fernández-Rodríguez, K. Rivera, A. Fernández-Cisnal, and D. Valcárcel-Paz participated in data acquisition and critically reviewed the content of the manuscript. All authors gave their final approval for the publication of the latest draft of the manuscript.

CONFLICTS OF INTEREST

None declared.

REFERENCES

INTRODUCTION

The presence of multivessel disease, defined as angiographic lesions with a percent diameter stenosis (PDS) ≥ 50% by visual estimation in patients with ST-segment elevation myocardial infarction (STEMI), is estimated to be approximately 50%.1 The COMPLETE trial compared angiography-guided preventive revascularization with stent implantation added to optimal medical therapy (OMT) for nonculprit lesions with a PDS ≥ 70% vs OMT alone.2 The trial found that angiography-guided preventive revascularization significantly reduced adverse cardiovascular events at 3 years of follow-up.2 Although the COMPLETE trial required physiological assessment using fractional flow reserve (FFR) for lesions with a PDS between 50% and 69% to guide the decision on revascularization, in practice, it was performed in only a very small percentage of patients.

The FLOWER-MI and FRAME-AMI trials3,4 investigated preventive stenting of FFR-guided nonculprit lesions—obtained through intracoronary pressure wire—compared with angiography-guided complete revascularization (visual estimation). Both trials mainly included intermediate lesions and demonstrated that pressure wire-guided preventive revascularization significantly reduces the need for revascularization, with similar or superior efficacy to angiography-guided complete revascularization.3,4 Despite these findings, clinical practice guidelines based on the COMPLETE trial recommend preventive stenting of nonculprit lesions guided by angiography alone.5,6

It is important to note that FFR is considered the gold standard for detecting myocardial ischemia (FFR ≤ 0.80). However, deferring treatment of nonculprit lesions that do not cause ischemia (FFR > 0.80) through OMT raises concerns in selected cases in which the anatomical features of the lesion suggest signs of vulnerability. In the FLOWER-MI trial, the group of patients randomized to undergo pressure-wire-guided revascularization with an FFR > 0.80 (referred for OMT) had more adverse events than those in the same group with FFR values ≤ 0.80 (referred for percutaneous revascularization).7 Several studies using intravascular imaging modalities have also demonstrated an association between the presence of fibro-lipid plaques with high lipid content and thin fibrous caps—known as vulnerable plaques—and the development of future adverse events due to plaque rupture.8,11

The VULNERABLE trial aims to evaluate the efficacy of a combined strategy using intracoronary physiological techniques and intravascular imaging to guide the treatment of intermediate nonculprit lesions in STEMI patients. The study hypothesis is that preventive stenting—in addition to OMT—in intermediate nonculprit lesions with FFR values > 0.80 and characteristics of vulnerable plaque will be superior to OMT alone. The present article includes the rationale and design of the study.

METHODS

Design

The VULNERABLE trial (NCT05599061) includes 3 groups based on the results obtained during the combined functional and anatomical assessment using pressure wires and optical coherence tomography (OCT). Figure 1 shows the study flowchart, which illustrates the 3 groups: patients with FFR ≤ 0.80 treated with stent (search failures), patients with FFR > 0.80 without vulnerable plaque characteristics (included in the registry group), and patients with FFR > 0.80 and vulnerable plaque characteristics (included in the randomized clinical trial).

This is a multicenter, controlled, prospective, randomized, parallel-group, single-blind study with patients included in the clinical trial group. The study will be conducted in accordance with the recommendations outlined in the Declaration of Helsinki on clinical research and has been approved by the lead ethics committee (Hospital Universitari de Bellvitge) and endorsed by the remaining ethics committees of participating centers. The participating centers and principal investigators are shown in table 1 of the supplementary data.

 

Table 1. Objectives of the VULNERABLE trial

Primary endpoint
Compare the percentage of TVF between the 2 groups of patients assigned to the randomized clinical trial (FFR > 0.80 with characteristics of vulnerable plaque by OCT): preventive revascularization with stent + OMT vs OMT alone
Key secondary endpoints
Compare the percentage of TVF between patients allocated to the registry group (FFR > 0.80 without characteristics of vulnerable plaque by OCT and treated with the OMT) and patients allocated to the randomized OMT group (FFR > 0.80 with characteristics of vulnerable plaque)
Other secondary endpoints
Compare the rate of all-cause mortality reported between the 2 subgroups of randomized patients
Compare the percentage of cardiac deaths reported between the 2 subgroups of randomized patients
Compare the percentage of all myocardial infarctions reported between the 2 subgroups of randomized patients
Compare the percentage of target vessel myocardial infarctions reported between the 2 subgroups of randomized patients
Compare the percentage of target vessel revascularization needs between the 2 subgroups of randomized patients
Evaluate the percentage of restenosis and stent thrombosis in the preventive revascularization group with stent + OMT of the randomized clinical trial
* Although all objectives are marked with a complete 4-year follow-up, an interim study will be conducted at 2 years. ** All objectives will be calculated on an intention-to-treat basis according to the statistical plan. An exploratory per-protocol analysis will also be conducted based on the assessment by the study’s core imaging laboratory.
FFR: fractional flow reserve; OCT: optical coherence tomograph; OMT: optimal medical treatment; TVF: target vessel failure.

 

The study has been entirely designed and initiated by researchers and is sponsored by the Spanish Society of Cardiology Working Group on Intracoronary Diagnostic Techniques, which includes a steering committee, a data and safety monitoring board, and an independent event adjudication committee. The members of these committees are listed in table 2 of the supplementary data. The steering committee and all study investigators are committed to accurate data collection and adherence to the study protocol. The funding entity (Abbott Vascular, United States) plays no role in the study design, data collection, analysis, or the writing of the study results. The study sponsor (Foundation for Education in Interventional Cardiology Procedures [EPIC]), along with the principal investigators, is responsible for data management and confidentiality.

 

Table 2. Inclusion and exclusion criteria of the VULNERABLE trial

Inclusion criteria
Patients older than 18 years
With STEMI (ST-segment elevation > 1 mm in, at least, 2 contiguous leads or true posterior ST-segment elevation with > 2 mm depression in anterior leads or new onset left bundle branch block) treated with successful revascularization of the culprit lesion within 72 hours from symptom onset
Presenting with multivessel disease with, at least, 1 angiographically intermediate lesion (PDS of 40% up to 69% by visual estimation) in a native vessel different from the culprit vessel
Planned FFR-guided percutaneous revascularization with a single 2.0 mm-to- 4.5 mm stent
Between 1 and 60 days after the index procedure (revascularization of the STEMI culprit vessel)
Exclusion criteria
Life expectancy < 4 years
Women of childbearing age who wish to become pregnant
Known intolerance to acetylsalicylic acid, heparin, everolimus, or iodinated contrast
Unresolved mechanical complications or infarct-related cardiogenic shock
Lesions suitable for the study located in the left main coronary artery, vessels with previous revascularization, in coronary bifurcations with > 2.5 mm side branches, severe angulations, or segments with severe calcification
History of severe asthma
Chronic kidney disease with glomerular filtration rate < 45 mL/min
FFR: fractional flow reserve; PDS: percent diameter stenosis; STEMI: ST-segment elevation myocardial infarction.

 

Endpoints

The primary objective of the VULNERABLE study (NCT05599061) is to compare the efficacy of preventive stenting combined with OMT vs OMT alone for intermediate lesions in noninfarct-related arteries with an FFR > 0.80 and vulnerable plaque characteristics as identified by OCT over a 4-year follow-up period. The primary endpoint of the study is the rate of target vessel failure (TVF), which is defined as a composite of cardiac death, target vessel myocardial infarction, or the need for target vessel revascularization.

The study also aims to evaluate several secondary endpoints, which are summarized in table 1. Among these secondary objectives, a key focus is the comparison of the TVF rate (the primary endpoint) between the registry group (patients with FFR > 0.80 without vulnerable plaque characteristics treated with OMT) and the randomized OMT arm of the clinical trial (patients with FFR > 0.80 and vulnerable plaque characteristics). The study endpoints are defined in table 3 of the supplementary data.12,13

Patient inclusion and exclusion criteria

The inclusion and exclusion criteria for the study are detailed in table 2. In brief, all patients with STEMI who have undergone successful revascularization of the culprit lesion and have at least 1 intermediate lesion (visually defined as having a DS of 40%-69%) in a noninfarct-related artery will be eligible for the study if percutaneous revascularization with a single stent guided by FFR is being considered. The study procedure must be conducted between 1 and 60 days after the revascularization of the culprit lesion. Patients must provide informed consent prior to the elective procedure for evaluating the nonculprit lesion.

Study protocol for nonculprit lesions and randomization

Eligible lesions will first be assessed with a pressure wire following the standard procedures in each center. Lesions with an FFR ≤ 0.80 will be considered search failures, and revascularization will be recommended based on clinical indications.5,6

Lesions with an FFR > 0.80 will be further evaluated with OCT according to the standard acquisition methods to detect vulnerable plaques in each center. The decision on whether a lesion meets the criteria for vulnerable plaque will be made by an accredited local investigator during the study procedure.

Patients with at least 1 lesion with an FFR > 0.80 without vulnerable plaque characteristics on OCT will be included in the registry group of the study. The protocol recommends OMT for all lesions with an FFR > 0.80 without vulnerable plaque characteristics. These patients will receive the same clinical follow-up as those in the randomized clinical trial group.

Patients with at least 1 lesion with an FFR > 0.80 that meets the criteria for a vulnerable plaque on OCT will be included in the clinical trial group. These patients will be randomized 1:1 to either preventive stenting combined with OMT or OMT alone (figure 1). Randomization will be conducted without stratification by center or clinical condition, using telematic algorithms. This process will be carried out online via the data collection platform provided by pInvestiga (Pontevedra, Spain).

Figure 1. Study diagram. FFR, fractional flow reserve; OCT, optical coherence tomography; OMT, optimal medical treatment; PCI, percutaneous coronary intervention; STEMI, ST-segment elevation myocardial infarction.

 

The supplementary data provide additional details on the FFR assessment method, including special situations where the lesion under study could not be fully evaluated, instances of unstable nonculprit plaques, complications related to diagnostic techniques, or patients with more than 1 nonculprit lesion.

Study device and implantation procedure

Patients with an FFR > 0.80 and vulnerable plaque characteristics identified by OCT assigned to the percutaneous coronary intervention group will be treated with an everolimus-eluting stent (Xience, Abbott, United States). According to the protocol, stent implantation must be guided by OCT. The criteria for OCT-guided stent implantation are detailed in table 4 of the supplementary data.

Optimal medical therapy

All patients included in both the randomized clinical trial and the registry must receive treatment in accordance with the European Society of Cardiology guidelines for managing acute coronary syndromes.5 The study protocol emphasizes managing modifiable risk factors—such as diet, smoking, obesity, exercise, and psychological status—as well as nonmodifiable risk factors, with set targets for blood pressure (systolic < 130 mmHg and diastolic < 80 mmHg), low-density lipoprotein cholesterol (< 55 mg/dL), and glycated hemoglobin A1c (< 7%). Pharmacological therapy should include beta-blockers and renin-angiotensin system inhibitors. Dual antiplatelet therapy is also recommended, but only during the first year after the index procedure, at the discretion of each center. As per the protocol, patient treatment details will be reported annually, and 2 lipid profile tests will be conducted throughout the study.

Vulnerable plaque criteria on optical coherence tomography and investigator training

Based on histopathological data, a plaque is defined as vulnerable when it is caused by a fibroatheroma with a large necrotic core composed of cellular debris and a high number of inflammatory cells, covered by a thin fibrous cap (≤ 65 µm).14 The criteria for identifying a vulnerable plaque in the study are adapted from the classic histopathological definition but modified for OCT assessment. These criteria are shown in figure 2.

Figure 2. Vulnerable plaque criteria by optical coherence tomography. EEM, external elastic membrane; minimal lumen area.

 

According to the protocol, 3 simultaneous criteria are required to define a vulnerable plaque by OCT:

The presence of a fibro-lipid plaque with a necrotic core covering more than 90º of the perimeter of the vessel over a length of more than 5 mm. A necrotic core is defined as a hypointense image with poorly defined borders that attenuates the OCT light beam, preventing visualization of the artery behind the core.

The presence of a thin fibrous cap, defined as ≤ 80 µm (65 + 15 µm axial resolution) in ≥ 3 consecutive images. The fibrous cap is defined as the tissue separating the necrotic core from the vessel lumen. Investigators will be trained to differentiate other findings that could be mistaken for a thin cap on OCT. Figure 3 shows examples of analogous OCT images that may mimic a thin fibrous cap but do not correspond to vulnerable plaques.

Figure 3. Distinction between vulnerable plaques and other findings by optical coherence tomography (OCT). A: plaque with superficial calcium (hypointense core with well-defined margins that do not attenuate the passage of light; arrow) and a thin fibrous cap. B: calcified nodule (arrow) protruding into the lumen and attenuating the signal, despite being composed of calcium. C: tangential signal loss (arrow) due to insufficient light beams caused by the peripheral, noncentral position of the OCT probe. D: superficial accumulation of macrophages (arrow) with a hyperintense appearance relative to the adjacent intima, with signal attenuation behind. E: presence of blood in the lumen due to inadequate flushing (arrow) during image acquisition, which distorts the arterial wall image, creating the appearance of hypointense regions. F: presence of blood between the probe and the OCT catheter (arrow) due to inadequate flushing, which distorts the arterial wall image and mimics hypointense regions.

Investigators will be required to measure a plaque burden of ≥ 70% in the cross-sectional area corresponding to the minimal luminal area (MLA) within the lesion. To perform this assessment, it is necessary to measure the vessel perimeter by delineating the external elastic membrane (EEM). Due to the difficulty of assessing the vessel perimeter in fibro-lipid plaques, especially at the MLA site, investigators will be trained to choose a section as close as possible to the MLA, where at least 60% of the vessel perimeter can be visualized if it is not possible at the same point. This allows for calculation using the following formula (figure 4):

Figure 4. Plaque burden assessment by optical coherence tomography. A: cross-section of the minimal lumen area. B: cross-section where the external elastic membrane (EEM) was measured. Since the EEM cannot usually be assessed in the cross-section corresponding to the MLA, an approximate estimation is made by measuring the EEM within 10 mm proximal or distal to the MLA (preferably distal) in the absence of side branches. The EEM will be assessed in the first cross-section where 60% of the EEM perimeter can be evaluated.

 

As per protocol, at least 1 local investigator from each participating center must have completed an online training course for the detection and assessment of vulnerable plaques using OCT, following the study criteria. Upon completing this course and passing a specific questionnaire, the investigator will be certified and approved to participate in the study.

Angiographic and optimal coherence tomography quantification analyses

The study includes an independent imaging laboratory for angiographic quantification and OCT analysis (Barcelona Cardiac Imaging Core Laboratory [BARCICORE-Lab]) to monitor adherence to the study criteria for diagnosing vulnerable plaques. A blinded analysis of the study results will be conducted, and patients will be assigned according to the protocol for exploratory analysis. A detailed explanation of the angiographic and OCT analysis conducted by the study laboratory is shown in the supplementary data.

Clinical follow-up and blinding

Patients in both the registry group and the randomized clinical trial group will undergo clinical follow-up for 4 years. Follow-up will include telephone consultations at 1 and 3 years, and in-person visits at 2 and 4 years. Each follow-up will involve an electrocardiogram and blood tests with cholesterol determination.

Patients in the randomized clinical trial group will be blinded to their assigned treatment group (single-blind). The details of blinding and monitoring are specified in the supplementary data.

Sample size calculation

The sample size has been calculated for the randomized clinical trial group. The number of patients included in the registry and search failures will depend on the total number needed to achieve the estimated sample size for the randomized trial.

According to previous studies on patients with acute coronary syndrome, theTVF rate for nonculprit lesions meeting vulnerable plaque criteria treated with OMT is estimated to be around 8% to 10% at 4 years. In similar lesions treated with stenting, the rate is approximately 4%.2,7,9 The studies used for the sample size calculation are summarized in table 5 of the supplementary data. Based on the study hypothesis, preventive stenting in nonculprit lesions with an FFR > 0.80 and vulnerable plaque characteristics is expected to reduce the primary endpoint by 60%. The estimated rate of TVF in the OMT group at 4 years is 10%. Assuming an annual loss to follow-up rate of 1.5% (total 6%), randomizing 600 participants 1:1 to preventive stenting plus OMT vs OMT alone will provide 80% power to demonstrate the superiority of preventive stenting with a 2-sided alpha error of .05.

Statistical analysis plan

The primary and secondary endpoints will be analyzed using the intention-to-treat principle at the 4-year follow-up. Comparisons will estimate event proportions between groups using logistic regression and will be reported as odds ratios with 95% confidence intervals. Only 1 event per patient will be counted for the primary endpoint. P values < .05 will be considered statistically significant for the primary endpoint. Kaplan-Meier curves will be used to visualize the time to the first event between groups.

For primary endpoint composites with missing data, a specific monitoring plan will determine if the missing data are random. In cases where data are adjudicated as missing at random, imputation methods will be used. For nonrandom missing data, sensitivity analyses using worst-case and last observation carried forward methods will be conducted.

Subgroup analyses will be performed for the primary and secondary endpoints, which involves comparing TVF rates between registry patients and those randomized to OMT in the clinical trial. Prespecified subgroups include: age > 75 years, sex, diabetes mellitus, left ventricular ejection fraction ≤ 35% at the time of the procedure, lesions in the proximal or mid-left anterior descending artery, and lesions in vessels with a reference diameter ≤ 2.75 mm.

Additionally, a hypothesis-generating parallel analysis will be conducted according to the study protocol. Patients will be included in the analysis only if the imaging laboratory confirms that their assigned treatment group, as determined by the local investigator, is consistent with the presence of vulnerable plaque identified by OCT. Patients will be excluded if there is a discrepancy between the investigator’s assignment and the imaging laboratory’s findings.

Interim analysis

After 2 years of follow-up, an interim analysis of the data is planned to monitor the primary endpoint in the randomized clinical trial group. Clinical follow-up will be extended if the events observed in the OMT arm of the randomized clinical trial are less than 4%.

DISCUSSION

The VULNERABLE trial aims to investigate the combined use of intracoronary physiology and images to guide the treatment of intermediate nonculprit lesions in STEMI patients.

Several lipid-lowering and anti-inflammatory drugs have been shown to reduce thrombotic events in patients with STEMI, likely by stabilizing functionally nonsignificant vulnerable plaques.15,17 In the PACMAN-AMI trial, treatment with alirocumab in addition to statins significantly reduced atheroma, decreased lipid content, and led to thickening of the fibrous cap compared with placebo in coronary regions with angiographically nonobstructive atherosclerosis (DS, 20%-50%).18 However, it is noteworthy that only 31% of patients in that study exhibited all 3 markers of reduced atherosclerosis, and data on more significant plaques (eg, 40%-69% stenosis with vulnerability criteria) were not specified.19

The use of stents in patients with vulnerable plaques is intended to enhance neointimal healing of the struts, which thickens the fibrous cap and stabilizes the plaque. The randomized PREVENT trial assessed the effectiveness of preventive stenting for functionally nonsignificant vulnerable lesions in patients with chronic coronary syndrome compared with OMT. Vulnerable plaques were identified using various intravascular imaging techniques, with most being guided solely by intravascular ultrasound. The study found that preventive stenting resulted in a statistically significant reduction in the rate of TVF at 2 years of follow-up (0.4% vs 3.4%; P = .0003).11

Finally, several observational trials have demonstrated that OCT is an effective method for detecting vulnerable plaques and monitoring the response to intensive treatments aimed at stabilizing these plaques through fibrous cap thickening.18,20 The PECTUS-obs trial included 438 acute coronary syndrome patients with nonculprit lesions with FFR > 0.80 treated with the OMT alone.10 All lesions were examined using OCT, with criteria similar to those used in the VULNERABLE trial to define vulnerable plaques. In that study, 34% of patients had at least 1 vulnerable lesion, which was associated with a higher risk of adverse events (15.4% vs 8.2% for the composite endpoint of death, myocardial infarction, or revascularization in the groups with and without vulnerable plaques, respectively). The VULNERABLE trial is the first to use OCT to guide the treatment of vulnerable plaques in functionally nonsignificant lesions.

CONCLUSIONS

The VULNERABLE trial aims to evaluate the effectiveness of preventive stenting plus OMT vs OMT alone for vulnerable plaques, as defined by OCT, in functionally nonsignificant intermediate lesions in nonculprit vessels of patients with STEMI. In addition, the study will provide information on the clinical relevance of the presence of vulnerable plaques in nonculprit lesions.

FUNDING

This study has been funded by Abbott Vascular.

ETHICAL CONSIDERATIONS

The study is being conducted following the recommendations outlined in the Declaration of Helsinki on clinical research, has been approved by Hospital Universitari de Bellvitge research ethics committee, and endorsed by the remaining ethics committees of participating centers. Informed consent acceptance and signature are required prior to performing any elective procedures to study the nonculprit lesion. Potential sex and gender biases are considered.

STATEMENT ON THE USE OF ARTIFICIAL INTELLIGENCE

No artificial intelligence was used in the drafting of this manuscript.

AUTHORS’ CONTRIBUTIONS

J. Gómez-Lara and E. Gutiérrez-Ibañes drafted this document. The remaining signatories reviewed the document, made changes at their discretion, and approved the final text.

CONFLICTS OF INTEREST

J. Gómez-Lara and E. Gutiérrez-Ibañes received a grant from Abbott Vascular for this study. A. Jurado-Román has received fees from Abbott, Boston, and Shockwave. E. Fernández received fees from Abbott and Hexacath. C. Cortés received a Río Hortega Contract from Instituto de Salud Carlos III. S. Brugaletta received fees from Abbott, Microport, and General Electric. T. García-Camarero received fees from Medtronic and Boston. J.A. Linares Vicente received fees from Abbott Vascular, Braun, AstraZeneca, Bayer, and IZASA. O. Rodríguez-Leor received fees from Shockwave, WorlsMedica, and Medtronic. S. Ojeda received fees from Abbott, Boston, WorldMedica, and Biosensors. A. Pérez de Prado received grants and fees from Abbot, Boston, iVascular, and Terumo. H.M. García-García received fees from ACIST, Boston Scientific, Medis, Biotronik, InfraRedx/Nipro, Chiesi, and Cordis. S. Ojeda and A. Pérez de Prado are associate editors of REC: Interventional Cardiology; the journal’s editorial procedure to ensure impartial processing of the manuscript has been followed. The remaining authors declared no conflicts of interest whatsoever.

REFERENCES