Immediate versus staged PCI in STEMI and multivessel disease: a systematic review and meta-analysis

INTRODUCTION

Coronary artery calcification constitutes a major challenge during percutaneous coronary intervention (PCI), as it reduces procedural success and increases the risk of complications. It limits optimal stent expansion, which predicts restenosis, stent thrombosis, and the need of target lesion revascularization.1-3 Several plaque modification techniques (PMT) have been developed to improve clinical outcomes in this setting. Rotational atherectomy has long been considered the standard approach for managing resistant calcified lesions. However, the development of newer technologies such as intravascular lithotripsy (IVL), together with increasing interest in excimer laser coronary atherectomy (ELCA), has expanded the range of available therapeutic options.4-7

The ROLLER COASTR-EPIC22 trial was the first randomized trial comparing rotational atherectomy, IVL, and ELCA in patients with moderate-to-severe calcified coronary lesions. Procedural success, safety and 1-year clinical outcomes were similar across all techniques.8

Elderly patients (≥ 75 years), who often present with increased comorbidity and complex coronary anatomy, remain underrepresented in clinical trials and may experience higher procedural risk and higher long-term mortality.9 In this post-hoc analysis of the ROLLER COASTR-EPIC22 trial, we assessed the impact of age on outcomes of PCI for moderately to severely calcified coronary stenosis treated with contemporary plaque-modification techniques. Specifically, we compared stent expansion, procedural success, in-hospital complications and 1-year clinical outcomes between patients < 75 and ≥ 75 years of age. Exploratory analyses of individual PMT within age strata were performed but were not powered for formal between-technique comparisons.

METHODS

Study design and population

ROLLER COASTR-EPIC22 trial was a multicenter randomized trial (NCT04181268) conducted at 8 high-volume centers in Spain.10 Complete inclusion and exclusion criteria, as well as the randomization process and procedural details, have been previously described.11 Briefly, eligible patients had moderate-to-severe calcification estimated by coronary angiography, and culprit lesions of ST-segment elevation acute coronary syndromes were excluded. All patients gave therir prior written informed consent before participation. Included patients were randomized 1:1:1 to rotational atherectomy, IVL, or ELCA from July 2019 through December 2023.10,11

Stratification and endpoints

This study is a post-hoc age-stratified analysis. Patients were stratified by age in 2 groups: < 75 years (n = 118) and ≥ 75 years (n = 53). Comparisons within age subgroups are exploratory and should be viewed as descriptive rather than confirmatory.

The primary endpoint was stent expansion assessed by optical coherence tomography (OCT), calculated as minimal stent area divided by the mean reference lumen area, analyzed according to the intention-to-treat principle.11

The secondary endpoints included angiographic success (final Thrombolysis in Myocardial Infarction grade-3 flow, assessed at both < 20% and < 30% residual stenosis), procedural success (angiographic success without major perioperative complications), clinical success (procedural success without in-hospital major adverse cardiovascular events [MACE]), device success (defined as achievement of adequate plaque modification with the initial device without the need for a second advanced PMT), minimal stent area by OCT, and in-hospital complications.11

Major perioperative complications were defined as death, perforation, flow-limiting dissection, abrupt vessel closure, or stent thrombosis. MACE was defined as the composite of cardiac death, target vessel myocardial infarction, target lesion revascularization, and definite/probable stent thrombosis.11

Procedures and imaging

Procedures have been previously described and followed latest European guideline recommendations.10 Pre- and post-PMT OCT imaging were recommended to characterize the lesion. Predilation with low-profile balloons was permitted to allow OCT catheter crossing prior to PMT. After plaque modification, drug-eluting stent implantation and optimization were performed, followed by the final mandatory OCT. OCT image acquisition and stent optimization protocols have been previously described.11

Rotational atherectomy, IVL and ELCA were performed according to current recommendations and device instructions, as previously described.6,12,13

Statistical analysis

The principal analyses were conducted in the intention-to-treat population. An additional analysis was performed in an as-treated fashion, based on the last PMT used. Continuous variables are expressed as mean ± standard deviation if normally distributed or median [IQR] otherwise, and categorical variables as counts and percentages. Between-group comparisons used the chi-square test or Fisher’s exact test for categorical variables and Student t test or Mann–Whitney U test for continuous variables. Noninferiority of IVL and ELCA vs rotational atherectomy for stent expansion was tested with a 1-sided t test against a prespecified noninferiority margin of −7%. This margin was adopted from the pivotal ROLLER COASTR-EPIC22 trial and was defined a priori by the steering committee as the smallest absolute difference in stent expansion considered clinically relevant, based on previous studies.11,14,15 Statistical significance was set at P < .05.10,11

Because this was an exploratory, post-hoc age-stratified analysis with a relatively small sample size in the elderly subgroup, no formal adjustment for multiple comparisons was applied. Given the large number of comparisons (2 age groups, 3 PMT and several procedural and clinical endpoints), conservative corrections such as Bonferroni would have markedly reduced statistical power and increased the risk of type II error. Instead, all effect estimates, 95% confidence intervals and exact P values are reported to allow readers to interpret the results with appropriate caution, and all subgroup findings are considered hypothesis-generating rather than confirmatory.

Given the low number of events, survival was assessed with Kaplan–Meier curves and log-rank tests. All statistical analyses were conducted using R version 4.3.2 (R Foundation for Statistical Computing, Vienna, Austria).

RESULTS

Patient allocation and baseline characteristics

A total of 171 patients were enrolled, of whom 118 (69%) were younger than 75 years (mean age, 66.8 ± 6.4 years; 79.5% male) and 53 (31%) were aged ≥ 75 years (mean age, 79.7 ± 3.7 years; 73.6% male). In patients < 75 years (n = 118), age was 66.8 ± 6.4 years (median, 68; IQR 64–71; range, 44–74), whereas in those ≥ 75 years (n = 53) age was 79.7 ± 3.7 years (median, 79; IQR 77–82; range, 75–89) (table S1 and figure S1).

Baseline clinical characteristics were broadly comparable between age groups, including rates of diabetes, hypertension, and prior revascularization. However, older patients had a lower prevalence of active smoking (15.1% vs 33.6%; P = .02), lower body mass index (27.0 ± 3.8 vs 28.5 ± 4.3 kg/m²; P = .04), and lower haemoglobin (12.8 ± 1.8 vs 13.5 ± 2.0 g/L; P = .04). No significant differences were observed in left ventricular ejection fraction, basal creatinine or clinical presentation, although elderly patients showed a trend towards a more frequent presentation as acute coronary syndrome (table 1).

Table 1. Baseline clinical characteristics

Angiographic and procedural data

Target vessels and lesion characteristics, including severity and length of calcification, were comparable across age strata and treatment arms. Most procedures were performed via radial access (> 80%), and treatment allocation was well balanced across age strata. Procedural duration, sheath size, and use of ad hoc PCI did not differ by age. Angiographic and procedural details are summarized in table S2.

OCT findings

The optional pre-plaque modification OCT was performed in 39 of 118 patients < 75 years (33.1%) and in 20 of 53 patients ≥ 75 years (37.7%), with no significant difference between age groups (P = .67).

Final OCT runs were obtained in more than 75% of patients. OCT parameters of calcification, assessed by an independent central core laboratory, consistently demonstrated a heavy calcium burden across all cases, with no significant differences between age groups or treatment modalities. OCT findings are presented in table S3.

Primary and secondary endpoints

No significant differences in terms of final stent expansion, minimal stent area, or final residual stenosis were observed between groups (table 2, figure S2). Angiographic, procedural, and clinical success rates exceeded 90% (considering < 30% residual percent diameter stenosis) in both age groups and did not differ by technique (table 2, figure 1).

Table 2. Procedural outcomes and complications

Figure 1. Angiographic, procedural, and clinical success of each technique. Angiographic success defined as final Thrombolysis in Myocardial Infarction grade-3 flow with < 30% residual percent diameter stenosis. Procedural success was considered angiographic success without major perioperative complications. Clinical success was defined as procedural success without in-hospital major adverse cardiovascular events.

Among patients ≥ 75 years, mean stent expansion values were broadly similar across the 3 PMT, and no statistically significant between-technique differences were detected; however, 95%CI, were wide because of the small sample size in each subgroup (table S3). Exploratory analyses of mean differences in stent expansion between techniques yielded results that were directionally consistent with the overall ROLLER COASTR-EPIC22 trial but were clearly underpowered in this age-stratified cohort and should be interpreted as hypothesis-generating only (figure 2 and table S4).

Figure 2. One-year MACE-free survival. Kaplan-Meier curves showing 1-year freedom from MACE in the intention to-treat population. MACE was defined as the composide endpoing of cardiac death, target vessel myocardial infarction, target lesion revascularization, stent thrombosis. MACE, major adverse cardiovascular events.

Overall, device success rate was 88.3% overall and was similar by age: < 75 (89.7%) vs ≥ 75 years (85.7%); P = .76. The causes of crossover differed by device: as in the pivotal trial, in the rotational atherectomy arm most crossovers were prompted by inadequate lesion dilation after atherectomy, whereas in the IVL and ELCA arms the primary driver was inability to cross the lesion with the dedicated balloon or laser catheter (figure S3 and table S5). In-hospital complication rates (perforations, bleeding, death) were low and balanced by age (table 2).

In 1-year follow-up (table 3, figure 2), patients aged ≥ 75 years had a markedly higher rate of MACE than those < 75 years (11.3% vs 1.7%; P = .01). All-cause mortality was also greater in the older cohort (9.4% vs 0.9%; P = .01).

Table 3. One-year event rates

Although less frequent, each individual component of the composite endpoint was numerically higher in patients ≥ 75 years without reaching statistical significance: cardiac death (11.3% vs 0%; P = .1), target vessel myocardial infarction (3.8% vs 0%; P = .1), target lesion revascularization (3.8% vs 0.8%; P = .23), target vessel revascularization (7.5% vs 1.7%; P = .08) and stent thrombosis (3.8% vs 0%; P = .10).

In a multivariable logistic regression including age ≥ 75 years, anemia, acute coronary syndrome presentation and renal dysfunction, age ≥ 75 years remained the strongest predictor of 1-year endpoints. For MACE, age ≥ 75 years was associated with an adjusted OR, 7.4 (95%CI, 1.5–53.9; P = .02), whereas none of the other covariates showed a clear independent association with the composite endpoint. For all-cause mortality, the adjusted OR for age ≥ 75 years was 10.7 (95%CI, 1.5–218.7; P = .04) and none of the other covariates demonstrated a clear independent effect. These findings are presented in table S6 and figure S4.

DISCUSSION

In this post-hoc age-stratified analysis of the ROLLER COASTR-EPIC22 trial and its 1-year follow-up, we observed that the overall safety and efficacy of PMT appeared consistent across age groups. However, at 1 year older patients experienced significantly higher rates of MACE (11.3% vs 1.7%; P = .01) and all-cause mortality (9.4% vs 0.9%; P = .01) despite comparable in-hospital complication rates.

After adjustment for anemia, acute coronary syndrome presentation, and renal dysfunction, age ≥ 75 years remained associated with higher adjusted odds of both 1-year MACE and all-cause mortality. None of the adjustment covariates demonstrated a clear independent effect, suggesting that unmeasured factors closely related to aging, such as frailty, are likely to account for much of the excess risk observed in older patients.

Randomized evidence directly comparing contemporary PMT in calcified coronary disease remains scarce. The ROLLER COASTR-EPIC22 trial was the first trial to randomize patients among rotational atherectomy, IVL, and ELCA.10 Previous device-specific studies and registries have demonstrated the feasibility of each technique, but none had evaluated all 3 within a single randomized framework.16-18

Coronary calcium is independently associated with long-term mortality risk, and age is not only a key predictor of coronary calcification but also an independent predictor of MACE, regardless of calcium burden.19 Nevertheless, elderly patients are underrepresented in PMT studies, leaving limited evidence to guide the choice of the optimal PMT strategy. Regarding rotational atherectomy, there is little evidence in elderly patients, but retrospective data suggests similar success and in-hospital complication rates compared with younger individuals.20 Similarly, the BENELUX-IVL prospective registry demonstrated the safety profile and technical success of IVL in patients aged ≥ 80 years.21 ELCA, however, has not been specifically studied in the elderly population.

Selecting elderly patients for revascularization requires balancing benefits and risks. Comorbidities (anemia, chronic kidney disease, acute coronary syndrome) and limitations in physiological reserve increase complexity and may reduce revascularization uptake in this population.22,23 Our findings support that chronological age alone should not preclude revascularization, as PMT appeared effective and safe when performed by experienced operators, regardless of age. These results, however, should be interpreted cautiously given the limited sample size and exploratory, post-hoc nature of the age-stratified analysis. The importance of operator experience in PMT for complex scenarios has been highlighted by the CRATER trial program, which evaluated rotational atherectomy in patients with chronic kidney disease and severely calcified lesions and reported high procedural success but also substantial perioperative and long-term event rates, largely reflecting the extreme baseline risk of this population.24,25

Notably, our analysis suggests no excess perioperative complications in older adults, although the study was not powered for subgroup comparisons and 95%CI, were wide, particularly in the elderly ELCA subgroup. We advocate for meticulous patient selection, based on preoperative risks and comorbidities; however, PMT should be used when necessary for adequate lesion preparation to maximize stent expansion and avoid suboptimal implantation, a known driver of adverse clinical events.

In our cohort, elderly patients achieved similar procedural success, stent expansion and in-hospital safety outcomes vs younger patients yet experienced a markedly higher rate of 1-year MACE and all- cause mortality. This pattern is consistent with the e-ULTIMASTER and MOSCA FRAIL trials, in which frailty, rather than age per se, emerged as the main determinant of adverse outcomes in older adults undergoing PCI.26,27 Taken together, these data support that revascularization decisions in elderly patients should not rely exclusively on chronological age, but should incorporate assessment of frailty, functional capacity and comorbidity to individualize the benefit–risk balance of an invasive strategy. The lack of formal frailty indices in our study therefore represents an important limitation. Future trials in elderly patients undergoing complex PCI should prospectively integrate standardized frailty tools to better guide patient selection and tailor treatment.

In the subset of patients with available baseline OCT, we did not observe relevant differences in calcium burden or morphology nor in angiographic severity or extent of disease, between patients < 75 and ≥ 75 years. This suggests that the underlying calcific process is biologically similar across age groups, even if it becomes clinically manifest at different ages, and is consistent with the comparable postoperative stent expansion and minimal stent area observed in both strata. Nevertheless, despite similar stent optimization, the ≥ 75-year group showed a numerically higher rate of definite/probable stent thrombosis and cardiovascular death at 1 year (3.8%), which is clinically meaningful in this context. As underexpansion alone is unlikely to fully explain these events, age-related factors such as greater comorbidity and frailty, a prothrombotic milieu and a reduced myocardial reserve, may have contributed to the excess risk observed in older patients, even after apparently adequate angiographic and OCT-guided results.

Contemporary randomized PMT trials (such as ROTAXUS, PREPARE-CALC, ISAR-CALC 2 or ECLIPSE ) enrolled patients with a mean age around 70 years, but none of them reported age-specific outcomes for those ≥ 75 years, limiting its applicability to older populations.28-32 Our analysis contributes to fill this knowledge gap suggesting procedural success and safety of PMT in the elderly. However, due to the nonprespecified nature of our analysis, these results should be considered hypothesis-generating. Future randomized studies should integrate objective frailty and functional measures and include sufficient follow-up to assess both procedural and long-term outcomes in this growing population.

Study limitations

This study has several limitations to consider. First, it was a post-hoc analysis and the findings should be regarded as hypothesis- generating rather than definitive. Second, because age stratification was not prespecified in the trial design, the study was not statistically powered for subgroup comparisons based on age, and the relatively small number of patients aged ≥ 75 years may limit the generalizability of the results.

Third, frailty status and functional capacity –both known to strongly influence outcomes in elderly patients– were not assessed, which limits the clinical granularity of the findings.

Fourth, the study was not powered to detect differences in clinical events and results should be interpreted cautiously due to the limited number of events.

Fifth, posttreatment OCT images were not available in slightly more than 20% of patients, with a higher proportion of missing studies in the ≥ 75-year group. This pattern of missing data may introduce selection bias, as patients without analyzable postoperative OCT could differ systematically from those with complete imaging, potentially limiting the internal validity and generalizability of the stent expansion findings, particularly in the elderly subgroup.

Sixth, randomization was based on angiographic calcification alone, without prior evaluation of lesion crossability or balloon dilatability, which could have impacted the need for secondary PMT. Indeed, some patients required a second PMT, complicating the interpretation of the intention-to-treat analysis, although complementary as-treated and per-protocol analyses were performed to mitigate this limitation. Additionally, not all patients underwent complete pre- and post-PCI OCT, which may have influenced both device selection and the assessment of stent expansion metrics.

Seventh, the 1-year follow-up provides only mid-term outcome data and does not address long-term endpoints such as stent durability or the need for target lesion revascularization. Lastly, the trial was conducted in high-volume centres by experienced operators, which may limit the applicability of these results to lower-volume settings or institutions with less experience in complex PCI and PMT.

CONCLUSIONS

In this age-stratified analysis of the ROLLER COASTR-EPIC22 trial, elderly patients undergoing PCI for calcified coronary lesions achieved similar procedural success, stent expansion, and in-hospital safety outcomes as younger patients. However, patients aged ≥ 75 years experienced significantly higher rates of MACE and all-cause mortality at 1 year (figure 3).

Figure 3. Central illustration. Senior-ROLLER: age-related outcomes of plaque modification in coronary stenosis. Procedural success, stent expansion, and major procedural complications were similar in patients < 75 and those ≥ 75 years; however, the 1-year MACE and all-cause mortality rates were higher in the elderly, which highlights the need for careful patient selection and individualized treatment strategies. BARC, Bleeding Academic Research Consortium; ELCA, excimer laser coronary atherectomy; IVL, intravascular lithotripsy; MACE, major adverse cardiovascular events; RA, rotational atherectomy.

DATA AVAILABILITY

The data that support the findings of this study are available from the corresponding author upon reasonable request.

FUNDING

The ROLLER COASTR-EPIC22 trial was supported by an unrestricted grant from Fundación EPIC.

ETHICAL CONSIDERATIONS

This is a subanalysis of the ROLLER COASTR-EPIC22 trial (NCT04181268), which was approved by the institutional ethics committee at each participant center and conducted in full compliance with the principles outlined in the Declaration of Helsinki. The authors confirm that written informed consent was obtained from all participants before enrolment.

Sex and gender aspects were considered according to the Sex and Gender Equity in Research (SAGER) guidelines.

STATEMENT ON THE USE OF ARTIFICIAL INTELLIGENCE

Artificial intelligence was not used in this manuscript.

AUTHORS’ CONTRIBUTIONS

J. Vila-García and M. Basile contributed equally to the manuscript and share first authorship. J. Vila-García and M. Basile contributed equally to several phases of the study, including conception and design, and acquisition, analysis and interpretation of the data. In addition, J. Vila-García contributed to the drafting of the original manuscript and to the writing and revision of the final version, while M. Basile was primarily responsible for the critical review of the article. A. Gómez-Menchero, J. Caballero-Borrego, B. Rivero- Santana, G. Galeote, I.J. Amat-Santos, S. Jiménez-Valero, G. Miñana, S. Ojeda, A. Gonzálvez-García, D. Tébar-Márquez, S. Camacho- Freire, J. Zubiaur, R. Ocaranza-Sánchez and A. Domínguez participated in the acquisition of the data and in the review and editing of the final text. A. Jurado-Román and R. Moreno participated in the conception and design of the study, in the acquisition, analysis and interpretation of the data, in the drafting, review, editing and approval of the final manuscript, and in the overall supervision of the project. A. Jurado-Román was responsible for funding and administration. All authors approved the final version of the manuscript.

CONFLICTS OF INTEREST

S. Ojeda and R. Moreno are associate editors of REC: Interventional Cardiology; the journal’s editorial procedure to ensure impartial handling of the manuscript has been followed. A. Jurado-Román is a proctor for Abbott, Boston Scientific, World Medica, and Philips; has received consulting fees from Boston Scientific and Philips; and has received speaker fees from Abbott, Boston Scientific, Shockwave Medical, Philips, and World Medica. S. Ojeda has received consulting fees from Medtronic and Edwards Lifesciences; and has received speaker fees from Abbott, Boston Scientific, Philips, and World Medical. All other authors report no relationships relevant to the contents of this article to disclose.

ACKNOWLEDGMENTS

We thank the ROLLER COASTR-EPIC22 trial investigators, coordinators, and participating patients for their dedication.

SUPPLEMENTARY DATA

REFERENCES

INTRODUCTION

Chronic total occlusions (CTO) are common among patients undergoing coronary angiography and represent one of the most technically demanding scenarios for percutaneous coronary intervention (PCI). Although contemporary CTO PCI programs achieve high success rates,1 these procedures frequently require prolonged fluoroscopy time, dual arterial access,2,3 and sustained patient immobility. In addition, ischemia-related chest discomfort may occur during complex procedural strategies.4,5

Anxiety is common in patients undergoing coronary procedures in the cath lab and may contribute to procedural discomfort and the need for pharmacologic sedation or analgesia.6-8 In routine practice, premedication and intraoperative administration of benzodiazepines or opioids are often used to mitigate anxiety and pain; however, their benefits are modest, and pharmacologic strategies and their use varies across centers.9 CTO PCI may be particularly associate with anxiety due to its typical duration, access strategy, and potential for procedural chest pain.

Virtual reality (VR) is an immersive audiovisual distraction strategy that can reduce procedural pain and anxiety across clinical settings. A systematic review demonstrated that VR-based distraction is effective for pain reduction in multiple procedural contexts.10

In interventional cardiology, early evidence suggests feasibility and potential benefit of VR during procedures performed under conscious sedation, including transcatheter aortic valve implantation and atrial fibrillation ablation.11,12 However, there are no randomized data evaluating VR during CTO PCI, a setting in which nonpharmacologic anxiolysis could be particularly valuable.

The ReViCTO trial was designed to test whether VR use during elective CTO PCI reduces the maximum level of patient-reported procedural anxiety vs usual care. Secondary endpoints included procedural pain, the use and dose of intraoperative anxiolytic or analgesic drugs, and patient satisfaction with the VR intervention. Figure 1 summarizes the main findings.

Figure 1. Central illustration. ReViCTO trial overview and main findings. Elective CTO PCI is a prolonged, technically complex procedure frequently associated with patient anxiety and discomfort. In the ReViCTO randomized trial (N = 59), patients were assigned to immersive audiovisual distraction using VR goggles (n = 31) or usual care (n = 28). VR use was feasible and well tolerated but did not significantly reduce peak procedural anxiety (VAS 0–10) or pain or intraoperative sedative or analgesic requirements vs usual care; 80.6% of VR patients reported willingness to use VR again in a future intervention. CTO, chronic total occlusion; PCI, percutaneous coronary intervention; VAS, visual analogue scale; VR, virtual reality.

METHODS

Trial design and oversight

The ReViCTO trial is an investigator-initiated, single-center, randomized, controlled, open-label, superiority trial with 2 parallel groups comparing immersive VR goggles vs usual care during elective CTO PCI. The study received no external funding. The rationale and full trial design have been published previously.13

The trial was conducted in accordance with the Declaration of Helsinki and International Conference on Harmonization Good Clinical Practice guidelines. The protocol was approved by the Clinical Research Ethics Committee of Hospital Clínico Universitario de València on 28 February, 2022, and all patients gave their prior written informed consent. The trial was registered at ClinicalTrials.gov (NCT05458999).

Participants

Adults (age > 18 years) scheduled for elective CTO PCI at Hospital Clínico Universitario de València were screened for eligibility. Key exclusion criteria were any condition precluding VR use, such as significant visual impairment, dementia, language barrier (inability to communicate fluently in Spanish or English), or other circumstances preventing safe use of the headset. Eligibility criteria were prespecified in the protocol publication.13

Randomization and trial procedures

Patients were randomized in a 1:1 ratio to the VR group or the control group using computer-generated permuted blocks to reduce the risk of imbalance in group sizes in a small trial.14 Allocation concealment was implemented via a web-based application that generated a unique trial identification number and assigned treatment arm after enrollment, preventing post-randomization modification or deletion. Due to the nature of the intervention, no blinding was applied to participants, operators, or outcome assessors.

CTO PCI was performed according to contemporary clinical practice by an experienced CTO team. Pharmacologic management of anxiety and pain was not protocolized and was left to the discretion of the primary operator in both groups. Specifically, morphine chloride and/or midazolam could be administered on demand during the procedure according to observed or reported anxiety or pain, in accordance with the trial protocol.

Interventions

Virtual reality group

A commercially available head-mounted display (Oculus Quest 2, Meta Platforms, United States) was used. Participants viewed the documentary series Our Planet via a video-streaming application (Netflix) in a virtual “theater” environment, starting with episode 1 with sequential autoplay thereafter, as specified in the protocol. The headset was applied before arterial puncture and was maintained throughout the intervention unless the patient requested removal or a serious complication occurred. Patient status was monitored at regular intervals during the procedure.

Control group

Participants assigned to control underwent CTO PCI under usual care without VR goggles.

Outcomes

The prespecified primary endpoint was the maximum level of anxiety perceived by the patient during the procedure, assessed immediately after the procedure and before leaving the cath lab using a visual analogue scale for anxiety (VASa). Secondary endpoints included maximum patient-perceived pain during the procedure (VASp), the use and total dose of intraoperative anxiolytic or analgesic drugs (midazolam and morphine chloride), procedure-related nausea or dizziness, and patient satisfaction with the VR intervention, including willingness to use VR again. Endpoint definitions and timing of assessment followed the protocol publication.

For analysis, VAS scores were treated as numeric ratings ranging from 0 (none) to 10 (worst), consistent with the trial questionnaires and the observed data range. Baseline angina-related health status was measured using the Seattle Angina Questionnaire (SAQ) to contextualize symptom burden.15

Data collection and management

Demographic characteristics, medical history, comorbidities, baseline symptom status (including SAQ), and procedural characteristics (arterial access strategy, procedure duration, fluoroscopy time, and radiation dose metrics) were collected from institutional electronic health records and procedure reports, supplemented by direct patient interview when necessary. Immediately after completion of CTO PCI, a trained study nurse administered the postoperative questionnaire and recorded VAS anxiety and pain, as well as nausea, dizziness, and satisfaction items. Intraoperative administration of morphine and midazolam and their total doses were recorded contemporaneously by the study nurse.

Data were entered into a dedicated electronic database incorporating range checks for numeric variables and duplicate checks for hospital identifiers and stored on a restricted-access workstation as described in the protocol.

Sample size estimation

The target sample size (58 patients, 29 per group) was calculated based on the primary endpoint, assuming a common standard deviation of 2.7 points for VAS anxiety and aiming to detect an absolute between-group difference of at least 2 points with a 2-sided alpha of 0.05 and 80% power. The standard deviation assumption was informed by prior cath lab anxiety studies.9,16

Statistical analysis

Continuous variables are expressed as mean (standard deviation, SD) or median (interquartile range, IQR) as appropriate (for the primary endpoint and Japan Chronic Total Occlusion (J-CTO) score, both measures are reported to allow comparison with sample size assumptions and to account for non-normal distribution). Categorical variables as counts and percentages. Between-group comparisons were performed using the Student t test for normally distributed continuous variables and the Mann–Whitney U test otherwise; categorical variables were compared using Fisher’s exact test or the chi-square test, as appropriate. Post hoc, we performed an analysis of covariance (ANCOVA) model with VASa as the dependent variable and treatment group as the main effect, adjusting for baseline anxiety. As a sensitivity analysis, we additionally adjusted for intraoperative opioid and benzodiazepine administration. Finally, to address the randomization imbalance in angiographic complexity, a multivariable linear regression analysis was conducted with maximum procedural anxiety as the dependent variable, adjusting for baseline anxiety and the J-CTO score. All tests were 2-sided, with a significance threshold of P < .05. Analyses were performed using R (V. 4.3.2, R Foundation for Statistical Computing, Austria). Reporting followed CONSORT guidelines for trial conduct and prespecified analyses (checklist in the supplementary data).17

RESULTS

Patients

Between 1 March 2022 and 23 October 2025, a total of 119 scheduled CTO PCI were performed. Fifteen patients declined the use of the headset, and in 44 cases the VR device was not available. One patient was excluded due to visual impairment (blindness). Overall, 59 patients were randomized to VR goggles (n = 31) or usual care (n = 28), as shown in figure 2.

Figure 2. Study flow diagram. CTO PCI, percutaneous coronary intervention for chronic total occlusion; VR, virtual reality.

Enrolment was prospective; however, randomization was contingent on operational availability of the VR system. Early in the study, a single trained investigator was responsible for device preparation and operation, so randomization could only occur when this investigator was present in the cath lab (eg, during vacations or other clinical/research commitments). From June 2023 onward, a second investigator was trained, increasing coverage. In addition, the VR system was out of service for approximately 2 months due to changes in the required internet infrastructure. Importantly, nonrandomization during these periods was driven by logistical constraints rather than patient characteristics.

Baseline characteristics

Baseline clinical characteristics were broadly similar between groups. Median age was 67 [60;70] years in the VR group and 60 [58;66] years in the control group, and most participants were men (29 [93.5%] vs 26 [92.9%]). The prevalence of hypertension (51.6% vs 60.7%) and diabetes (41.9% vs 46.4%) was comparable; dyslipidemia was numerically less frequent in the VR group (58.1% vs 82.1%). Baseline anxiety assessed before entering the cath lab was moderate and did not differ significantly between groups (VAS anxiety: mean ± SD, 3.35 ± 3.10 vs 4.21 ± 3.05; P = .289; median [IQR], 2 [0; 6] vs 5 [2; 6]). Baseline pain was minimal in both groups (VAS pain baseline: 0.06 ± 0.36 vs 0.00 ± 0.00; P = .346; median [IQR], 0 [0 to 0] in both). Baseline angina-related health status was similar. The SAQ score was 52.4 [36.3; 64.3] in the VR group and 50.0 [44.0; 64.3] in the control group (P = .475), as shown in table 1.

Angiographic complexity differed between groups. The J-CTO score was higher in the VR group (mean ± SD, 3.10 ± 1.11; median [IQR], 3 [2; 4]) than in the control group (2.32 ± 1.36; median [IQR], 2 [1; 3]) (Student t test P = .019; Mann-Whitney U test P = .040).

Procedural characteristics and clinical outcomes

The distribution of procedural approach (antegrade, retrograde, or hybrid) was similar between groups (P = .826). Procedural duration, fluoroscopy time, radiation dose-area product, and contrast volume were not significantly different between groups, although radiation exposure tended to be higher in the VR group.

Technical success was achieved in 25 of 31 patients (80.6%) in the VR and 25 of 28 patients (89.3%) in the usual care group (P = .477). Procedural complications occurred in 4 of 31 patients (12.9%) in the VR group and 4 of 28 patients (14.3%) in the control group (P = 1.00) (table 1).

Table 1. Baseline characteristics, lesion and procedural characteristics

Primary endpoint

The primary endpoint (maximum procedural anxiety; [VASa]) and key secondary endpoints (maximum procedural pain [VASp] and intraoperative drug administration) were available for all randomized participants.

Maximum procedural anxiety did not differ significantly between groups. Mean VASa was 3.23 ± 2.78 with VR and 3.75 ± 2.77 with usual care (mean difference, −0.52 points; 95% confidence interval (95%CI), −1.97 to 0.92; Student t test P = .472). Median [IQR] values were 4 [0; 5] and 4 [2; 6], respectively. Because the VASa distribution was skewed, results were consistent using the Mann–Whitney U test (P = .379) (figure 3, table 2 and table S1).

Figure 3. Patient-reported procedural anxiety and pain, and intraoperative drug use. A: maximum procedural anxiety assessed immediately after the procedure using a visual analogue scale for anxiety (VASa; 0–10). B: maximum procedural pain assessed using a visual analogue scale for pain (VASp; 0–10). C: total intraoperative dose (mg) of midazolam and morphine by treatment group; zero values indicate no drug administration. In panels A and B, dots represent individual patients; the right-side estimation plot shows the mean between-group difference (VR minus usual care) with its 95% confidence interval. P values correspond to prespecified between-group comparisons. VAS, visual analogue scale; VR, virtual reality.

Table 2. Endpoints and safety

In a post hoc ANCOVA adjusting for baseline anxiety, VR was not associated with lower peak procedural anxiety (adjusted mean difference, −0.21; 95%CI, −1.62-1.20; P = .773). Results remained consistent after additional adjustment for intraoperative morphine and midazolam dose (table S1 and table S2).

Given the significantly higher angiographic complexity in the VR group, a sensitivity analysis was conducted using multivariable linear regression. After adjusting for J-CTO score and baseline anxiety, the effect of VR on procedural anxiety remained non-significant (adjusted coefficient -0.40; 95%CI, -1.81 to 1.02; P = .576). In this model, procedural complexity was not independently associated with patient-reported anxiety (P = .370); see table S1.

Secondary endpoints

VASp was similar in the 2 groups: 3.68 ± 3.39 with VR and 3.64 ± 2.33 with usual care (mean difference, 0.03; 95%CI, −1.50-1.57; P = .964). Median [IQR] values were 4 [1; 6] and 4 [2; 5], respectively (P = .777).

Intraoperative pharmacologic treatment did not differ between groups. Morphine was administered to 14 of 31 patients (45.2%) in the VR group and 13 of 28 (46.4%) in the control group (P = 1.00). Total morphine dose (including zero valus for nonuse) was 2.74 ± 3.61 mg and 2.00 ± 2.71 mg, respectively (P = .379). Midazolam was administered to 2 of 31 patients (6.5%) in the VR group and 3 of 28 (10.7%) in the control group (P = .661), with total midazolam doses of 0.29 ± 1.19 mg and 0.50 ± 1.95 mg, respectively (P = .617) (figure 3 and table 2).

Safety and acceptability

Symptoms potentially attributable to VR were uncommon. Nausea occurred in 1 patient (3.2%) in the VR group and in no patients in the control group (P = 1.00). Dizziness occurred in 1 patient (3.2%) in the VR group and in no patients in the control group (P = 1.00).

Among patients assigned to VR, 25 of 31 (80.6%) reported that they would be willing to use a relaxation video again during a future intervention; 5 (16.1%) would not, and 1 (3.2%) was uncertain.

DISCUSSION

We conducted a randomized trial to evaluate whether VR-based audiovisual distraction during elective CTO PCI can improve the patient experience. Several key findings emerge. First, VR did not meaningfully reduce patient-reported peak procedural anxiety, and pain outcomes were similarly neutral, arguing against a clinically relevant anxiolytic or analgesic effect with the intervention as delivered. Second, VR did not reduce the use of intraoperative opioid or benzodiazepine requirements, suggesting limited incremental benefit beyond contemporary usual care in the cath lab. Third, VR implementation appeared feasible and was not associated with signals of procedural harm, with overall procedural outcomes remaining comparable despite an imbalance toward greater angiographic complexity in the VR group. Finally, acceptability was generally high among patients assigned to VR, supporting its role as a patient-centered option for selected individuals even when average effects on anxiety are modest.

Interpreting the neutral result in the context of prior interventional cardiology VR trials

Several factors may explain the absence of a measurable anxiolytic effect in ReViCTO. First, peak procedural anxiety levels were relatively low, leaving limiting the potential for improvement and increasing the likelihood of a floor effect. A similar pattern has been observed in contemporary minimally sedated structural interventions, in which overall anxiety burden is modest and VR has not consistently produced detectable differences on global assessments.18

Second, anxiety and pain were assessed immediately after the procedure as a single recalled measure of peak intensity. Although pragmatic and consistent with the study protocol, this approach relies on retrospective recall and may underestimate brief, procedure-specific peaks of discomfort that are particularly relevant in CTO PCI, such as arterial puncture, prolonged immobility, complex device manipulation, or episodes of ischemic chest pain.19 Consequently, any benefit limited to these discrete high-stress intervals may have been diluted when summarized as a single postprocedural peak value.

Third, the VR content in the ReViCTO consisted of passive content (documentary viewing). Across procedural settings, the magnitude of VR’s effect appears to depend on how strongly the experience captures attention and induces relaxation. Interventions incorporating guided relaxation, hypnosis-based modules, or interactive elements have more consistently demonstrated larger and more reproducible effects than passive viewing alone.20-22

In the context of the broader interventional cardiology literature, the neutral effect of VR on peak intraoperative anxiety in ReViCTO is therefore less surprising. Existing cath lab and structural heart studies suggest that observable benefit depends on when VR is delivered, which patients are targeted, particularly those with higher baseline anxiety, and how outcomes are measured. In transcatheter aortic valve implantation (TAVI), early randomized studies reported lower VAS-based procedural anxiety, supporting feasibility and a potential anxiolytic effect.11 In contrast, a larger minimalistic TAVI randomized study found improvements in state anxiety (State-Trait Anxiety Inventory, state scale [STAI-S]) and perceived procedure duration, yet less consistent effects on VAS-based anxiety or pain, underscoring the influence of measurement instruments on signal detection.23 Evidence from coronary procedures is similarly nuanced. In the VR InCard program, which targeted patients with elevated preoperative anxiety and incorporated structured preprocedural sessions, the primary analysis was neutral but adjusted analyses suggested modest reductions, with heterogeneity by clinical context.24,25 Similarly, a randomized trial conducted before coronary angiography reported anxiety reduction using questionnaire-based assessments rather than a single recalled postoperative peak rating.26 Collectively, these data support the interpretation that VR may be most effective when targeted to patients with higher baseline anxiety, delivered during anticipatory or discrete high-stress phases, and evaluated using instruments sensitive to global state anxiety, rather than relying solely on a single recalled peak score.22,27

Pharmacologic co-intervention and post hoc adjustment

A key pragmatic feature of ReViCTO was that background anxiolysis and analgesia were not protocolized, reflecting real-world practice in the cath lab where conscious sedation and intraoperative comfort measures are typically individualized. This approach is consistent with contemporary cath lab randomized studies evaluating patient comfort under usual care conditions.28,29 In the final dataset, intraoperative morphine and midazolam use were similar, and dose distributions did not differ materially. To align with current analytic recommendations, we performed a post hoc ANCOVA adjusting peak anxiety for baseline anxiety, an approach that can improve precision when baseline values are prognostic.30 Baseline anxiety was strongly associated with peak anxiety, while VR assignment was not (adjusted VR effect approximately -0.32 VAS points; P = .64). Adding opioid and benzodiazepine doses did not materially change the VR estimate, supporting that the neutral primary result is unlikely to be explained by baseline imbalance or differential pharmacologic rescue. Baseline anxiety was higher in the usual care group; adjusted analyses yielded consistent findings.

Feasibility, tolerability, and patient-center implementation

From a feasibility standpoint, VR use in CTO PCI appeared safe and compatible with the cath lab environment, with nausea and dizziness reported rarely and no signal suggesting increased procedural instability. The practical challenge was tolerability during long procedures: early discontinuation of the headset occurred in 9 VR patients, which is consistent with broader evidence that fully immersive head-mounted displays can trigger discomfort or cybersickness in a minority of users, particularly with extended exposure.31 Implementation studies further indicate that device-related factors—such as physical interference, usability barriers, and the need for individual tailoring—can influence both uptake and sustained use, supporting a selective rather than universal deployment strategy.32 These observations support a patient-center approach: VR may be most useful when offered to patients with higher baseline anxiety, a clear preference for audiovisual distraction, or anticipated prolonged immobility, and when focused around discrete high-stress phases. Preoperative counseling remains essential with VR serving as a complementary, rather than substitutive, strategy.

Limitations

This trial has limitations that should be considered. First, it was a single-center, open-label study and subjective outcomes may be susceptible to reporting buas; however, randomization, standardized outcome collection, and consistently neutral findings across patient-reported outcomes and medication use make a major bias-driven effect unlikely. Second, recruitment was not consecutive and 12.6% of eligible patients declined participation, which may limit generalizability; nonetheless, this also reflects real-world acceptability of a wearable intervention, and the decliner rate is transparently reported. Third, anxiety and pain were assessed as a single postoperative peak rating rather than repeated measures during predefined high-stress phases; this approach was identical in both groups, and recalled peak experience remains clinically relevant for satisfaction and willingness to undergo future procedures. Fourth, anxiolysis and analgesia were not protocolized and were operator-directed, potentially attenuating any incremental benefit of VR. Nevertheless, this pragmatic design improves applicability and bailout medication was systematically recorded. Fifth, VR content was passive and exposure time likely varied due to early discontinuation; the intention-to-treat analysis therefore estimates the real-world effect of offering VR. Finally, although angiographic complexity (J-CTO score) was higher in the VR group, multivariable analyses indicated this imbalance did not explain the neutral anxiety results and complexity was not a significant predictor of distress in this cohort. Benzodiazepine amnesia may attenuate recall; midazolam use was low and balanced.

CONCLUSIONS

In this randomized trial of patients undergoing elective CTO PCI, although immersive VR was feasible and well tolerated, it did not reduce patient-reported peak intraoperative anxiety or pain, or the need for intraoperative morphine or midazolam vs usual care.

FUNDING

None declared.

ETHICAL CONSIDERATIONS

The protocol was approved by the Clinical Research Ethics Committee of Hospital Clínico Universitario de València (28 February, 2022), and all participants gave their prior written informed consent. Sex distribution is reported, and reporting adhered to SAGER guidelines to mitigate potential sex- and gender-related bias.

STATEMENT ON THE USE OF ARTIFICIAL INTELLIGENCE

Generative artificial intelligence was used to support language editing and formatting of the revised manuscript. No artificial intelligence tools were used to analyze study data. All content was reviewed and approved by the authors, who take full responsibility for the manuscript.

AUTHORS’ CONTRIBUTIONS

A. Fernández-Cisnal and B. Silla conceived the study and designed the trial. A. Fernández-Cisnal, B. Silla, C.E. Vergara-Uzcategui, J.M. Ramón, E. Valero, and C. Romero Menor contributed to patient inclusion and data acquisition. A. Fernández-Cisnal performed the statistical analyses and drafted the manuscript. B. Silla, C.E. Vergara- Uzcategui, J.M. Ramón, E. Valero, C. Romero Menor, J. Núñez, V. Bodí, and G. Miñana critically revised the manuscript for important intellectual content. All authors approved the final version and agreed to be accountable for all aspects of the work.

CONFLICTS OF INTEREST

None declared.

SUPPLEMENTARY DATA

REFERENCES

INTRODUCTION

Calcified nodules (CN) represent a significant challenge during percutaneous coronary intervention (PCI), as their mechanical resistance limits effective lesion preparation and adequate stent expansion, resulting in suboptimal angiographic outcomes and a higher risk of adverse clinical events.1-7

Intracoronary optical coherence tomography (OCT) is highly effective for the detection and characterization of coronary calcium, offering superior sensitivity and specificity than angiography. Robust evidence demonstrates that OCT-guided PCI improves both procedural and clinical outcomes, supporting guideline recommendations for its use in complex coronary lesions.8-11

Several dedicated devices and techniques have been developed to facilitate calcium modification and optimize lesion preparation. Among these, intravascular lithotripsy (IVL) has emerged as a widely adopted strategy for the treatment of CN because of its ease of use, low complication rates, and favorable outcomes in recent studies.2,3,7,12

Alternatively, orbital atherectomy (OA) has been shown to be an effective strategy for the treatment of severely calcified and non- dilatable coronary lesions. However, evidence regarding its performance in CN remains limited and is largely derived from small observational studies and case reports.1,12-23

Despite major advances in imaging and plaque-modification technologies, the optimal management strategy for CN remains uncertain.

METHODS

Population and study design

The ORBIT-SHOCK pilot study is a multicenter, prospective, investigator-initiated randomized pilot study, sponsored by the Spanish Society of Cardiology. It will include patients diagnosed with atherosclerotic disease with evidence of CN identified by OCT, causing significant angiographic stenosis eligible for revascularization through PCI.

A CN, as identified by OCT, is defined as a localized protruding mass within the coronary artery wall that appears as a signal-poor region with sharply delineated borders. An eruptive CN is characterized by an accumulation of small calcium fragments that protrude through and disrupt the overlying fibrous cap, typically associated with small amount of thrombus. In contrast, a noneruptive CN is defined as an accumulation of small calcium fragments covered by a smooth intact fibrous cap without overlying thrombus.1

Inclusion and exclusion criteria are detailed in table 1. The selection of eligible patients will be conducted by the investigators at each participant center. Following confirmation of the presence of a CN and verification of compliance with the inclusion criteria, and absence of exclusion criteria, patients will be randomized in a 1:1 ratio to 1 of the 2 lesion preparation strategies under study: OA or IVL (figure 1). Randomization will be stratified according to the type of CN (eruptive or noneruptive) to ensure a balanced distribution across treatment groups. Randomization occurs immediately after OCT confirmation of the presence of CN and before any plaque-modification strategy has been started.

Table 1. Inclusion and exclusion criteria

Figure 1. Central illustration. ORBIT-SHOCK study design and flow chart. Eligible patients will be selected by investigators at each participant center. After confirmation of the presence of a CN and verification of compliance with the inclusion criteria, and exclusion of any exclusion criteria, patients will be randomized in a 1:1 ratio to 1 of the 2 lesion preparation strategies under investigation: OA or IVL. Randomization will be stratified according to the type of CN (eruptive or noneruptive) to ensure a balanced distribution across treatment groups. CN, calcified nodule; IVL, intravascular lithotripsy; NSTEACS, non-ST-segment elevation acute coronary syndrome; STEACS, ST-segment elevation acute coronary syndrome; OA, orbital atherectomy; OCT, optical coherence tomography; PCI, percutaneous coronary intervention.

Endpoints

All endpoints are detailed in table 2 and defined in table S1. The primary endpoint is the percentage of stent expansion at the CN site, assessed by OCT and defined as the ratio between the minimum stent area (MSA) at the CN site and the reference area at the CN site:

Table 2. Study endpoints

Stent expansion at the CN site (%) = (MSA at the CN site / reference lumen area at the CN site) x 100

The stent reference area at the CN site will be manually calculated by CoreLab specialists using co-registered pre- and post-stent images. Additionally, stent expansion will also be assessed using the Aptivue automated software (Abbott, United States). Specific methodological details regarding the selection of reference cross- sections and algorithms used to calculate stent expansion are described in the methods section of the supplementary data.

Secondary endpoints include procedural and strategy success, and mechanistic OCT-derived parameters related to calcium modification, including nodule debulking volume and calcium fracture. Additional OCT metrics of final stent optimization will also be assessed, including minimum stent area, stent ellipticity, significant malapposition, and residual nodule protrusion. Finally, clinical outcomes including target lesion failure, target lesion revascularization, and major adverse cardiovascular events will be assessed at the 12-month follow-up.

Study devices and procedures

The recommendations for the use of OA and IVL have been established according to the SCASI Expert Consensus Statement.24 Only CE-marked devices locally approved and commercially available will be used in the study.

The study procedures and their sequence are illustrated in figure 2.

Figure 2. Study procedures. Red numbers indicate OCT acquisitions. 1. The presence of a CN must be confirmed by optical coherence tomography before enrolling a patient with suggestive angiographic findings. OCT imaging before any intervention on the target lesion is mandatory. Predilation with a 1.5 – 2.0 mm balloon is permitted if the OCT catheter cannot cross the lesion. 2. Lesion preparation with OA or IVL according to randomization. 3. Obtaining OCT images after the use of OA or IVL is mandatory, provided it is feasible and the patient’s clinical condition permits it. 4. Prior to stenting, dilation with a 1:1 NC balloon dilation is mandatory. 5. Stenting (use of a next-generation everolimus-eluting stent with CE marking is recommended). Stent optimization through post-dilation with an NC balloon based on OCT images is mandatory. 6. Final OCT images after stenting and optimization must be obtained to document the final procedural result. CN, calcified nodule; DES, drug-eluting stents; IVL, intravascular lithotripsy; NC, noncompliant; OA, orbital atherectomy; OCT, optical coherence tomography.

Optical coherence tomography

The presence of a CN must be confirmed by OCT before including a patient with suggestive angiographic images.

OCT imaging must be obtained before any intervention on the target lesion. Limited predilation with a 1.5–2.0 mm balloon is permitted if the OCT catheter cannot cross the lesion. This minimal predilation is intended solely to facilitate catheter delivery while minimizing structural modification of the nodule and preserving the accuracy of the baseline morphological assessment. OCT acquisition immediately after OA/IVL and after stenting (final result) is mandatory, provided it is technically feasible and the patient’s clinical condition allows it. Although not mandatory, performing an OCT run after 1:1 balloon predilation and immediately prior to stenting is highly recommended to confirm adequate plaque preparation and obtain accurate measurements of the reference vessel diameter and required stent length. Stent optimization through post-dilation with a noncompliant (NC) balloon based on OCT images is mandatory. In such cases, a repeat OCT acquisition must be performed to document the final procedural result.

Orbital atherectomy

A smooth forward and backward motion at a slow advancement speed (approximately 1.0 mm/s) is required to optimize ablation efficiency. For vessels with a reference diameter ≥ 3.0 mm, the use of high rotational speed (120 000 rpm) is strongly recommended. For vessels < 3.0 mm, low rotational speed (80 000 rpm) should be used initially. Operators should aim for the maximum feasible number of passes (typically > 5) to maximize lumen gain, ensuring that individual treatment runs do not exceed 30 seconds to prevent thermal injury. The total treatment time with a single crown should not exceed 5 minutes. Before stenting, dilation with a 1:1 NC balloon is mandatory.

Intravascular lithotripsy

The IVL balloon should be sized 1:1 to the reference vessel diameter to ensure efficient energy transfer. Pulses: delivery of the maximum number of pulses (up to the catheter limit) is strongly recommended to ensure adequate modification of the CN. Appropriate rest periods between therapy cycles are required to allow for distal washout and prevent hemodynamic compromise. Before stenting, dilation with a 1:1 NC balloon is mandatory.

Lesion stenting

To ensure greater treatment homogeneity, the use of a next-generation everolimus-eluting stent with CE marking is recommended. If this is not feasible, the use of another next-generation stent with CE marking is permitted.

Crossover between techniques and the management of special situations are detailed in the procedures section of the supplementary data.

Data collection

A clinical evaluation will be performed and data will be collected at 3 predefined time points: at patient enrollment, at hospital discharge, and at 12 months after PCI (table 3). All data will be recorded in an electronic case report form (eCRF).

Table 3. Study visits and data collection

OCT images will be analyzed by a central core laboratory, which will remain blinded to the lesion modification technique employed. The core laboratory will be responsible for providing accurate and standardized interpretations, thereby ensuring unbiased results regardless of the treatment strategy applied.

Statistical considerations

Sample size

The limited number of studies specifically addressing CN, together with the heterogeneity in patient selection criteria and methods used to calculate stent expansion, makes it challenging to estimate the sample size required to ensure adequate statistical power. To address this limitation, a pilot study has been designed with 50 patients (25 per group) to evaluate and compare the outcomes of OA and IVL in this clinical setting.

The determination of this sample size was primarily driven by feasibility and pragmatic considerations to ensure the successful completion of the pilot study. Despite this pragmatic approach, the planned sample of 50 patients provides an estimated statistical power (0.8) to detect a clinically relevant difference of 12% in stent expansion under an exploratory superiority framework, assuming an expected standard deviation of ± 15%.

Descriptive statistics and hypothesis testing methodology

The normality of continuous variables will be assessed using the Kolmogorov-Smirnov test. Comparisons of normally distributed quantitative variables between treatment groups will be performed using the Student t test. For ordinal variables or continuous variables that do not follow a normal distribution, the non-parametric Mann-Whitney U test will be used. Qualitative variables wil be compared using the chi-square test or Fisher’s exact test. P values < .05 will be considered statistically significant.

Datasets

The intention-to-treat (ITT) analysis set will include all randomized patients, regardless of the treatment ultimately received.

The per-protocol (PP) analysis will include patients who received the treatment as assigned at randomization and met all inclusion criteria. Patients with major protocol deviations, including those who underwent crossover, will be excluded from this analysis.

The as-treated analysis set will include patients analyzed according to the treatment they actually received, rather than the treatment to which they were originally randomized.

Primary endpoint analysis

The primary endpoint of stent expansion at the CN site will be analyzed using an ITT approach, with results being expressed as mean and SD or median and IQR if the data deviate from normal distribution. In addition to the ITT analysis, the primary endpoint will also be assessed in the PP and as-treated sets.

Secondary endpoint analysis

The analysis of procedure-related secondary endpoints will be conducted initially in the ITT set, followed by assessments in the PP and as treated sets. The rate of clinical endpoints (target lesion revascularization, target lesion failure, major adverse cardiovascular events) will be compared between the 2 treatment groups using Cox proportional hazards regression, and event-free survival curves will be estimated using the Kaplan-Meier method. Differences in the primary endpoint between groups will be evaluated using adjusted hazard ratios with 95% confidence intervals and P values derived from Cox regression.

Hierarchical analysis using the win ratio method

Given that the trial includes multiple secondary endpoints that may influence the clinical course, an exploratory efficacy analysis comparing the 2 strategies will be performed using a hierarchical win-ratio method.

The first outcome in the hierarchy will be stent expansion at the CN. A “win” for one group will be defined as stent expansion at least 10 percentage points greater than that observed in the comparator patient. For this analysis, percent expansion will be truncated at a maximum of 100% prior to comparison. In the event of a tie, the procedure will proceed to the next predefined hierarchical endpoint, sequentially assessing procedural/strategy success, rate of major adverse cardiovascular events, stent malapposition at the CN, stent ellipticity, CN protrusion into the stent lumen, and minimum stent lumen area.

The overall win ratio will be estimated as the ratio of the total number of wins between the 2 treatment groups. Statistical significance will be assessed using the Finkelstein–Schoenfeld method with a 2-sided P < .05.

Analysis of predictors of adverse events

Predictors of suboptimal angioplasty outcomes will be evaluated using logistic regression models. Predictors of adverse clinical events during follow-up will be assessed using Cox proportional hazards regression models.

Adjusted analyses

Multivariable regression models will be used adjusted for CN type (eruptive vs noneruptive) and for any baseline or procedural differences observed between the groups.

Predefined subgroup analyses

Predefined subgroup analyses will include CN type (eruptive vs noneruptive), sex, vessel size (≥ 3.0 mm vs < 3.0 mm), and calcium length (≥ 15 mm vs < 15 mm).

Interim analysis

Once enrollment of all patients has been completed, an interim analysis will be performed. This analysis will focus on the primary endpoint (stent expansion at the CN site, assessed by OCT) as well as procedure-related secondary endpoints. The statistical analysis will be performed using STATA 18 (StataCorp, LLC, United States).

Ethical considerations

The ORBIT-SHOCK trial is conducted in full compliance with the Declaration of Helsinki and the principles of Good Clinical Practice. The study protocol was approved by the central Clinical Research Ethics Committee of Hospital Universitario Ramón y Cajal (Madrid, Spain) and subsequently by the ethics committees of all other participant centers. All patients provide written informed consent before enrollment and randomization. Furthermore, the study was designed and is reported in accordance with the SAGER guidelines. Measures have been implemented to promote equitable participant inclusion and to minimize sex and gender bias. Sex-disaggregated data will be collected and analyzed to assess potential differences in procedural and clinical outcomes between men and women. The ORBIT-SHOCK pilot study is registered at ClinicalTrials.gov with the identifier NCT06736665.

DISCUSSION

Coronary calcification in the form of CN is consistently associated with worse outcomes due to the difficulty if achieving adequate calcium fracture and vessel expansion before stenting.

IVL has emerged as a commonly used strategy for the treatment of CN. However, although stent expansion > 100% is achieved in many patients, nodule fractures are observed in only a minority of cases, and nodule deformation occurs in less than half. As a result, stents expansion is often asymmetric, and residual nodule protrusion into the stent lumen is present in most patients. These findings could potentially increase the risk of future adverse events during follow-up.

The mechanism of action of OA may provide particular advantages for the treatment of CN. First, the rotational movement of the crown enables debulking of the nodule, while the orbital movement allows for circumferential modification of the vessel wall without being constrained by the guidewire position within the vessel.

Despite the theoretical advantages of its mechanism of action for treating CN, a recent observational study specifically comparing OA and IVL in these lesions did not demonstrate superior outcomes for OA.23 The study reported similar efficacy between the 2 techniques in terms of stent expansion (90.0% for OA vs 92.5% for IVL) and minimum lumen area (5.6 mm2 vs 5.5 mm2), as well as comparables rates of target lesion failure at 2 years (12.0% for OA vs 9.8% for IVL). Although the authors performed a propensity score-matched analysis, the sample size remained limited. In addition, given the retrospective design of the data, the presence of unmeasured confounding and significant differences in baseline lesion complexity are highly likely. In real-world clinical practice, atherectomy devices are preferentially used for uncrossable or more extensively calcified lesions, inherently introducing selection bias.

Moreover, in that study, the median number of OA runs was only 4 (IQR, 3-5) for a median calcium length of 25 mm, and the rotational speeds were not reported. This limited number of passes may be insufficient to achieve adequate lesion preparation and debulking of a CN, which often requires a higher number of runs and high rotational speeds.24 Only a randomized controlled design can ensure a homogeneous and balanced cohort, allowing an unbiased comparison of both strategies. Accordingly, the ORBIT-SHOCK pilot study will be the first randomized trial designed to directly compare OA and IVL for the treatment of CN, with all procedures performed under a strict, OCT-guided protocol and mandatory stent optimization.

Sample size determination and rationale for a randomized pilot study

Several studies have evaluated stent expansion after angioplasty using intracoronary imaging modalities. In the ILUMIEN II study, the minimum stent expansion in the OCT-guided group (calculated using the mean of the proximal and distal reference lumen areas) was 72.8% (IQR, 63.3 - 81.3).25 This corresponds to an estimated standard deviation (SD) of 13.3%, assuming a normal distribution. In the ILUMIEN IV trial, minimum stent expansion in the OCT-guided group was 80.8 ± 16.8%.9

Previous retrospective registries evaluating IVL or OA have reported wide SDs in stent expansion, ranging from 16.5% to > 27%. 1,3,4,17,20 A recent observational study comparing IVL and OA specifically for the treatment of CN reported SDs for stent expansion ranging from 13.0% (in eruptive nodules treated with IVL) to 25.9% (in noneruptive nodules treated with OA)12. This marked variability may be largely attributed to the heterogeneity of treated lesions, small sample sizes, heterogeneous definitions of the reference lumen area, or the lack of standardized imaging protocols. In contrast, the ORBIT-SHOCK pilot trial incorporates a strict OCT-guided PCI protocol with mandatory stent optimization. Under these controlled conditions, operator-dependent is expected to be substantially reduced. Consequently, an estimated SD of ± 15%, consistent with monitored trials such as ILUMIEN IV, was consiered the most appropriate assumption.

Regarding the clinically meaningful effect size, several pivotal trials, such as ULTIMATE,26 ILUMIEN III,27 and OPINION,28 have used a stent expansion threshold > 90% as the standard for optimal stent deployment, a target associated with significantly lower rates of target lesion failure during follow-up. Furthermore, the DOCTORS trial demonstrated that stent expansion < 79.4% predicts a fractional flow reserve < 0.90, suggesting a sub-optimal hemodynamic result. Accordingly, and acknowledging that achieving > 90% expansion may not be feasible in a significant proportion of complex lesions, the EAPCI expert consensus document proposes > 80% expansion as a pragmatic target for routine clinical practice.29 A 12% difference in stent expansion may therefore have important clinical implications, potentially shifting outcomes from an optimized result to a range associated with less functional outcomes.

Given the limited and heterogeneous data currently available, this pilot study was pragmatically sized to assess feasibility while maintaining sufficient exploratory power to detect a clinically relevant 12% difference in stent expansion. These findings will provide the essential methodological foundation and variance estimates necessary of future large-scale confirmatory trials.

Study limitations

Focusing on patients with CN (which account for approximately 20%–40% of severely calcified lesions) and the potential excluding of individuals with impaired renal function due to the contrast requirements of OCT may limit the eligible study population. These strict inclusion criteria could therefore result in a slower recruitment rate than initially anticipated. Nevertheless, participation of 6 centers, with an estimated enrollment rate of 1 patient per center per month, is expected to allow completion of patient recruitment within the planned timeframe.

The distinct behavior of eruptive and noneruptive CN, both in terms of stent expansion and the occurrence of adverse events during follow-up, could introduce bias if the distribution of these 2 subtypes is not balanced between treatment groups. To mitigate this risk, stratified randomization has been implemented to ensure a balanced allocation of both CN types across the treatment arm.

CN rarely occur in isolation and are frequently associated with extensive background coronary calcification. To address this, the study protocol specifically recommends applying the randomized technique to treat all concomitant calcified lesions within the target segment. This may include performing multiple OA runs or using more than 1 IVL balloon when necessary, with the explicit objective of achieving optimal lesion preparation and final results throughout the entire lesion length, not only at the nodule site. Although the primary endpoint focuses on stent expansion at the CN site, broader secondary clinical outcomes may be influenced by the overall calcific burden of the treated segment. Nevertheless, the randomized design of the study is expected to evenly distribute this anatomical complexity between the 2 treatment arms.

Finally, as a pilot clinical trial with a sample size determined primarily by feasibility, this study is not statistical powered to detect small differences between OA and IVL. However, the exploratory superiority framework is design to detect a clinically relevant effect size, such as a 12% difference in stent expansion. The fundamental purpose of this pilot study is to establish the methodological foundation and generate the preliminary data required to design future, adequately powered confirmatory trials.

CONCLUSIONS

The ORBIT-SHOCK pilot study will be the first randomized trial to allow a direct comparison of the outcomes of OA and IVL in the management of calcified CN, a common and complex clinical scenario that requires robust evidence from randomized clinical trials.

FUNDING

The study was funded by an unrestricted institutional research grant from Abbott (United States).

ETHICAL CONSIDERATIONS

The ORBIT-SHOCK trial is conducted in full compliance with the principles outlined in the Declaration of Helsinki and the principles of Good Clinical Practice. The study protocol was approved by the central Clinical Research Ethics Committee of Hospital Universitario Ramón y Cajal (Madrid, Spain) and subsequently by the ethics committees of all other participant centers. All patients gave their written informed consent before enrollment and randomization. Furthermore, the study was designed and is being reported following the SAGER guidelines. We have implemented measures to ensure an equitable inclusion of participants and avoid sex/gender bias. Sex-disaggregated data will be collected and analyzed to evaluate potential differences in procedural and clinical outcomes between men and women.

STATEMENT ON THE USE OF ARTIFICIAL INTELLIGENCE

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

AUTHORS’ CONTRIBUTIONS

L.M. Domínguez-Rodríguez: conceptualization, original draft, review, and editing. J. Bayón Lorenzo, I. Amat Santos, J. Martín Moreiras, J. Valencia Martín, M. Pan, L. Salido Tahoces, A. Pardo Sanz, J.L. Mestre-Barceló, A. Larrea-Iñarra, J.M. Ruiz-Nodar, A. Diego Nieto, C. González-Juanatey: drafting, review, and editing. J.L. Zamorano, and Á. Sánchez-Recalde: conceptualization, drafting, review, and editing. All authors have reviewed and approved the final version of this manuscript.

CONFLICTS OF INTEREST

None declared.

SUPPLEMENTARY DATA

REFERENCES

INTRODUCTION

Percutaneous coronary intervention (PCI) with drug-eluting stents (DES) is the current standard of care for coronary revascularization in patients with coronary artery disease (CAD).1 Despite substantial advances in stent technology, the permanent presence of metal scaffolding presents a persistent hazard of stent-related adverse events (e.g.,, stent failure).2 These events occur in ~2% of patients per year and persist over time, thereby limiting long-term outcomes.3,4 Drug-coated balloons (DCB) have emerged as an attractive “leave-nothing-behind” alternative when an optimal angiographic result is achieved,5,6 delivering antiproliferative drugs directly into the arterial wall without leaving a permanent implant, potentially promoting arterial healing, preserving vessel anatomy, and avoiding stent-related complications.7,8 DCB have demonstrated efficacy in the treatment of in-stent restenosis,9,10 an accumulating evidence supports their use in selected settings, such as small-vessel disease (SVD) and bifurcation lesions.11-13 However, their role in de novo coronary lesions remains controversial. Randomized controlled trials (RCT) evaluating DCB have often been limited by small sample sizes, heterogeneous populations, variable procedural protocols, and reliance on surrogate angiographic endpoints.14 Notably, the 2 largest RCT published to date have yielded conflicting results, leaving the comparative efficacy of DCB vs DES unresolved.15-16

We conducted a systematic review and pairwise meta-analysis of RCT to assess the efficacy and safety profile of DCB vs DES for the treatment of de novo coronary lesions.

METHODS

This meta-analysis was prospectively registered in PROSPERO (CRD4202458794) and followed the PRISMA and Cochrane Collaboration guidelines (tables 1S and S2).17 Ethical approval was waived given the nature of the study.

Eligibility criteria

Studies were eligible if they: a) enrolled patients undergoing PCI for de novo coronary artery lesions of any vessel size; b) randomized participants to DCB angioplasty or DES implantation; and c) reported at least one outcome of interest. Exclusion criteria included: a) absence of a second- or third-generation DES as the primary comparator; and b) evaluation of DCB as part of a hybrid or combined strategy with concomitant stent implantation. No language restrictions were applied.

Search strategy, study selection, data extraction, and qualitative assessment

Three electronic databases (PubMed, Web of Science, and Scopus) were searched from inception to 29 October 2025 (table S1). Additional sources included society websites, conference proceedings, and reference lists of eligible studies. Two reviewers (R. Rinaldi and K. Bujak) independently screened titles and abstracts, assessed full texts for final inclusion, and extracted trial- and arm-level data into standardized spreadsheets. Disagreements were resolved by consensus. When multiple reports referred to the same trial, the one with the longest follow-up was selected. Study quality was assessed using the Cochrane Risk of Bias 2 tool.18 Publication bias was evaluated using funnel plots and Egger’s test, with adjustment using the trim-and-fill method for endpoints suspected of publication bias.

Study endpoints

The prespecified primary endpoint was trial-defined target lesion revascularization at the longest follow-up. When target lesion revascularization was not reported, target vessel revascularization was used as the closest available reported revascularization endpoint. Secondary endpoints included target vessel revascularization, myocardial infarction (MI), target-vessel MI, vessel thrombosis, cardiac and all-cause mortality, major adverse cardiovascular events (MACE), and major bleeding. When multiple definitions of the same endpoint were reported within a trial, we extracted the definition most closely aligned with standardized Academic Research Consortium criteria (eg, clinically driven target lesion revascularization).19,20 Angiographic endpoints included binary restenosis, late lumen loss (postoperative minus follow-up minimal luminal diameter), minimal luminal diameter, diameter stenosis, and net luminal gain (follow-up minus preoperative minimal luminal diameter).

Statistical analysis

Analyses were performed on an intention-to-treat (ITT) basis. Pairwise meta-analyses were conducted using a frequentist random- effects models (DerSimonian-Laird estimator) to account for antici­pated biological variability. Binary outcomes were expressed as risk ratios (RR) with 95% confidence interval (95%CI), while continuous outcomes were reported as standardized mean differences (SMD). A continuity correction of 0.5 was applied when 0 events occurred in either study group. Heterogeneity was quantified using the Cochran Q test and I² statistic, interpreted as low (< 25%), moderate (25-50%), or high (> 50%). Baujat plots were used to identify influential studies. Statistical significance was defined as two-sided P < .05.

Prespecified subgroup analyses were performed by stratifying the trials according to study-level characteristics, including: a) drug type (paclitaxel vs sirolimus); b) lesion characteristics (SVD < 3.0 mm; large vessels; bifurcation; ST-segment elevation myocardial infarction culprit lesion); c) dual antiplatelet therapy (DAPT) duration (shorter in DCB group vs equal duration in both groups). Meta- regression analyses were conducted to assess the impact of confounding variables, including a) mean study-level reference vessel diameter; b) follow-up duration; and c) year of publication. Sensi- tivity analyses were performed for both the primary and secondary outcomes using alternative modeling approaches (eg, incidence rate ratios; trim and fill analysis, Bayesian random-effects meta-analysis with weakly informative priors), and by excluding studies: a) at high risk of bias or without ITT analysis; b) using paclitaxel-eluting stents as comparators; c) using ultrasound-guided DCB; d) reporting target vessel revascularization instead of target lesion revascularization or non-Academic Research Consortium primary endpoint definitions (eg, definitions other than clinically driven target lesion revascularization); e) using DCB devices other than most commonly tested one in included trials (SeQuent Please); or f) identified as principal contributors to heterogeneity. All analyses were conducted using R version 4.2.0 (R Foundation for Statistical Computing, Austria).

RESULTS

Study selection, baseline, and angiographic characteristics

The study selection flowchart is reported in figure S1. After screening, 13 RCT met the inclusion criteria and were included in the quantitative synthesis.11,12,15,16,21-29 Among these, 12 trials had already been published,11,12,15,21-29 and one was available only as a conference proceeding.16 Key trials characteristics are summarized in table 1. A total of 5 studies focused exclusively on SVD,11,12,25,27,28 4 on de novo lesions of any vessel size,15,16,23,29 3 on ST-segment elevation myocardial infarction,26,30,31 and 1 on bifurcation lesions.24 One trial evaluated a sirolimus-coated balloon,16 while the remaining 12 tested paclitaxel-coated balloons.11,12,15,21-29 The weighted mean clinical follow-up was 22.9 months, and the weighted mean angiographic follow-up (reported in 10 studies), 8.4 months. Available endpoints and definitions across included trials are reported in tables S2 and S3, respectively. Overall, 7776 patients were included (3896 DCB vs 3880 DES), of whom 46.0% presented with acute coronary syndrome. The weighted mean reference vessel diameter was 2.95 mm. The weighted mean minimum anticipated DAPT duration was 5.0 months in the DCB group and 5.9 months in the DES group (table 1). Baseline clinical, angiographic, and procedural characteristics are presented in tables S4 and S5. The risk of bias was high in 3 studies (imprecise reporting or deviation from the ITT analysis) and moderate in remaining studies due to the open-label design (figure S2). Publication bias was detected only for late lumen loss and minimal luminal diameter endpoints (figure S3).

Table 1. Key baseline characteristics across included randomized controlled trials

Primary endpoint

No statistically significant difference was observed between DCB and DES for target lesion revascularization (RR, 1.24; 95%CI, 0.79-1.95; figure 1), with high heterogeneity (I² = 54.8%).

Figure 1. Results of meta-analysis for the primary endpoint. 95%CI, 95% confidence interval; DCB, drug-coated balloon; DES, drug-eluting stent; RR, risk ratio. The bibliographical references cited in this figure correspond to: Spaulding,16 Gao et al.,15 Liu et al.,27 Ke et al.,24 Yu et al.,29 Wang et al.,21 Kawai et al.,25 Cortese et al.,28 Niehe et al.,22 Tian et al.,11 Jeger et al.,12 and Nishiyama et al.23.

Secondary endpoints

No statistically significant differences were observed between DCB angioplasty and DES implantation for target vessel revascularization (RR, 1.39; 95%CI, 0.91-2.13), MI (RR, 0.92; 95%CI, 0.71-1.19), target-vessel MI (RR, 1.09; 95%CI, 0.78-1.51), cardiac death (RR, 1.05; 95%CI, 0.75-1.48), all-cause mortality (RR, 1.05; 95%CI, 0.82-1.36), or MACE (RR, 1.05; 95%CI, 0.78-1.41) (figure 2 and figure S4A-G). DCB angioplasty was associated with a significantly lower risk of major bleeding vs DES implantation (RR, 0.65; 95%CI, 0.43-0.96), primarily in studies adopting shorter DAPT regimens for DCB-treated patients (figure 2 and figure S4H). However, the interaction test between treatment effect and DAPT duration was not statistically significant (figure S5I). Heterogeneity was low to moderate across endpoints, except for target vessel revascularization, which showed high heterogeneity (I² = 55.2%).

Figure 2. Forest plot presenting pooled effect estimates for the secondary clinical outcomes and binary restenosis. 95%CI, 95% confidence interval; DCB, drug-coated balloon; DES, drug-eluting stent; RR, risk ratio.

Angiographic endpoints

At angiographic follow-up, binary restenosis did not differ between groups (RR, 1.17; 95%CI, 0.75-1.83) (figure 2 and figure S4I). DES implantation was associated with significantly higher late lumen loss (SMD, −0.41; 95%CI, −0.61 to −0.21), minimal luminal diameter (SMD, -0.50, 95%CI −0.64 to −0.37) and net luminal gain (SMD, −0.61; 95%CI, −0.77 to −0.44) vs DCB angioplasty, whereas DCB angioplasty was associated with greater diameter stenosis vs DES (SMD, 0.32; 95%CI, 0.20 to −0.44) (figure 3; figure S6). Heterogeneity was low for most angiographic outcomes, except for late lumen loss, for which heterogeneity was high.

Figure 3. Forest plot presenting pooled effect estimates for angiographic outcomes. 95%CI, 95% confidence interval; DCB, drug-coated balloon; DES, drug-eluting stent; SMD, standardized mean differences.

Sensitivity and subgroup analyses

Subgroup analyses by DAPT duration showed no significant differences between DCB and DES for primary or secondary ischemic endpoints (figure S5A-H). Subgroup analyses stratified by clinical indication and DCB drug type (paclitaxel- vs sirolimus-coated balloons) also showed no significant interactions (figures S7,S8).

Meta-regression analyses showed consistent treatment effects across reference vessel diameter and follow-up duration (figure S9A,B). Meta-regression according to publication year identified an increasing risk of target lesion revascularization for DCB in more recent trials (figure S9C).

Sensitivity analyses confirmed the results of the primary analyses (figures S10-S15). After excluding the trial using paclitaxel-eluting stent in one-third of control patients, DCB was associated with a significantly higher risk of target vessel revascularization, with no other significant differences observed (figure S16). Bayesian sensitivity analyses were largely consistent with the frequentist results across endpoints. For major bleeding, the treatment effect remained directionally consistent but did not reach statistical significance (figure S17).

Baujat plots identified REC-CAGEFREE I trial15 as the principal source of heterogeneity for target lesion revascularization and target vessel revascularization, and the study by Gobic´ et al.26 for late lumen loss (figure S18). Excluding these studies yielded consistent pooled estimates with low heterogeneity (figure S19).

DISCUSSION

The main findings of our meta-analysis can be summarized as follows: a) DCB angioplasty for de novo lesions showed a comparable risk of target lesion revascularization to DES at a mean follow-up of 2 years; b) no increased risk of MI, target vessel revascularization, cardiac or all-cause mortality was observed with DCB vs DES; c) DCB angioplasty was associated with a significantly lower risk of major bleeding vs DES, although the interaction according to DAPT duration was not statistically significant; and d) from an angiographic perspective, DCB was associated with lower late lumen loss, whereas DES achieved larger minimal luminal diameter and net luminal gain, reflecting the mechanical scaffolding effect (figure 4).

Figure 4. Central illustration. Main results of the study. DCB, drug-coated balloon; DES, drug-eluting stent.

In recent years, the “leave-nothing-behind” concept has gained increasing attention as a strategy to reduce stent-related adverse events and promote physiological vessel healing.32 However, evidence for DCB use in de novo CAD remains limited and heterogeneous.14 Previous meta-analyses generally reported comparable outcomes between DCB and DES, but were frequently restricted to specific subgroups, such as SVD,33,34 large vessels,35,36 or acute MI,37 or included observational data or early-generation DES comparators.38,39 The recent ANDROMEDA individual-patient-data meta-analysis suggested a possible reduction in MACE with DCB in SVD, although its interpretation was limited by the inclusion of only a few RCT and the use of early-generation stents as the comparator group.40

In contrast, our meta-analysis, incorporating 2 large recent RCT,15,16 provides the most contemporary and comprehensive evidence to date. By encompassing a broad spectrum of vessel sizes, lesion complexities, and clinical presentations, it demonstrates the consistent efficacy of DCB angioplasty across diverse clinical settings. Compared with the recent meta-analysis by Niu et al.,41 the present analysis incorporates nearly twice the number of randomized clinical trials and > 4 times the number of patients, including 2 large contemporary trials not previously analysed. In addition, our study focuses exclusively on newer-generation DES and includes bleeding outcomes, dual antiplatelet therapy stratification, meta-regression, and Bayesian sensitivity analyses. Rates of target lesion revascularization were equivalent between DCB and new-generation DES, both at early and extended follow-up, confirming the sustained durability of the DCB strategy over time. These findings suggest that the absence of a permanent metallic scaffold does not compromise vessel patency at 2-year follow-up or predispose to late restenosis, thereby supporting the role of DCB as a valid and reliable alternative to DES for the treatment of de novo coronary lesions.32

Furthermore, our findings help to contextualize the results of the REC-CAGEFREE I trial, which failed to demonstrate the non-inferiority of DCB vs DES in non-complex, de novo coronary lesions.15 Indeed, REC-CAGEFREE I represented the main source of heterogeneity in our analysis, and its exclusion yielded results consistent with the overall pooled effect, markedly reducing heterogeneity. Several methodological aspects may explain this discrepancy. First, unlike most previous RCT that focused on specific subgroups (eg, SVD or ST-egment elevation myocardial infarction), REC-CAGEFREE I adopted an all-comer design and used a device-oriented composite endpoint as its primary outcome. Second, extensive lesion preparation with cutting or scoring balloons in > 60% of cases may have contributed to improved outcomes in the DES group by facilitating stent expansion and reducing restenosis, while also enhancing drug delivery and procedural success in the DCB group, thereby potentially attenuating differences between treatment strategies.42,43 Third, approximately 10% of patients in the DCB group required bailout stenting for significant dissections or residual percent diameter stenosis > 30%, yet were still analysed within the DCB group in both ITT and per-protocol analyses. This methodological choice may have biased results against DCB because these patients typically have higher risks of repeat revascularization due to complex lesions, suboptimal angioplasty results, or residual dissections.44 Importantly, it was not specified whether adverse events occurred in patients treated exclusively with DCB or in those receiving bailout DES, potentially conflating outcomes driven by stented segments. Conversely, in trials such as SELUTION De Novo, where provisional stenting was incorporated within the DCB strategy, the inclusion of DES in the experimental group may have diluted potential treatment differences under ITT analysis, thereby limiting the ability to detect superiority of systematic stent implantation. Finally, the open-label design could have introduced surveillance bias, with a potentially lower threshold for ischemia testing and repeat angiography in the DCB group. Notably, event curves began to diverge around 100 days, coinciding with the transition from telephone to in-person follow-up.44

Furthermore, nearly all trials included in this meta-analysis evaluated paclitaxel-coated DCB, except for the SELUTION DeNovo trial,16 which tested a sirolimus-coated balloon in a large, all-comer population. The consistent findings across studies, irrespective of the antiproliferative agent used, suggest a class effect of DCB in terms of safety and efficacy when compared with contemporary DES. Nonetheless, further head-to-head studies directly comparing paclitaxel- and sirolimus-coated balloons are warranted.

The angiographic findings provide mechanistic insights into the clinical results. While binary restenosis rates were similar, DES achieved lower diameter stenosis and greater minimal luminal diameter and net luminal gain, consistent with its mechanical scaffolding properties. In contrast, DCB demonstrated lower late lumen loss. However, the smaller immediate postoperative lumen with DCB angioplasty may partially account for the lower late lumen loss observed at follow-up. Nevertheless, this difference may also reflect the absence of a permanent metallic implant, potentially more physiological vessel remodelling, and differences in local drug delivery dynamics and antiproliferative efficacy at the treated segment.45 Thus, DES may provide an immediate luminal advantage, as reflected by the greater net luminal gain, which represents a more integrative angiographic parameter less influenced by differences in acute luminal gain. This advantage may be particularly beneficial in complex, calcified, or large-vessel disease. Conversely, DCB may be preferable when vessel compliance and healing are prioritized, such as in SVD, bifurcations, or in younger patients in whom long-term metal avoidance may be advantageous.46 These complementary characteristics suggest an individualized approach that balances the need for mechanical support with the benefits of a “leave-nothing-behind” strategy.

Finally, we observed a lower incidence rate of major bleeding with DCB angioplasty vs DES implantation. This difference was primarily observed in those studies adopting shorter DAPT regimens for DCB-treated patients, suggesting that abbreviated antiplatelet strategies may be safely feasible with DCB and may make this approach a valuable option for patients at high bleeding risk.46-48 However, these findings derive from subgroup analyses stratified according to DAPT regimens specified in the trial protocols rather than the actual DAPT durations received by patients and should therefore be interpreted with caution. Ongoing trials such as the DEBATE (NCT04814212) and the PICCOLETTO IV (NCT06535568) are expected to provide further insights on this issue, particularly in anticoagulated or high-bleeding-risk populations.

Given differences in costs and lack of clinical superiority of DCB vs DES at either short- or long-term follow-up, the value of DCB angioplasty will ultimately depend on identifying specific patient populations who may derive the greatest benefit from a “leave-nothing-behind” strategy, as well as on the results of longer-term studies. Importantly, our findings should be interpreted as evidence of comparable efficacy rather than superiority, and do not support the routine replacement of DES in unselected patients.

Limitations

The present meta-analysis has several limitations. First, a certain degree of heterogeneity was observed across the included randomized trials, largely driven by the REC-CAGEFREE I trial. Furthermore, all included randomized trials enrolled patients in whom both treatment strategies were considered technically feasible and clinically appropriate. Therefore, the study populations reflect selected procedural scenarios rather than unselected, real-world practice. Second, as this was a study-level meta-analysis, our analyses were limited to aggregate endpoints reported in the original publications. Definitions of major bleeding varied substantially across trials, and this heterogeneity may limit the interpretability and comparability of the observed bleeding signal. Third, an analysis stratified by clinical presentation was not feasible because several RCT either did not report event rates according to presentation or excluded one of these subgroups entirely. Fourth, the open-label design of all included studies may have introduced performance or ascertainment bias. Fifth, although nearly all DCB used in the included studies were paclitaxel-coated, DES comparators consisted of a mixture of “limus”-eluting and paclitaxel-eluting stents, which could have influenced relative efficacy estimates in favor of certain DES platforms. Sixth, potential publication bias was detected for angiographic endpoints, possibly reflecting selective reporting of angiographic follow-up data. Although trim-and-fill analyses yielded estimates consistent with the primary results, these surrogate endpoints should be interpreted with caution. Furthermore, as with any meta-analysis based predominantly on published data, the possibility of publication bias cannot be entirely excluded. Seventh, data from the conference proceedings reporting the results of the recent SELUTION De Novo trial,16 whose full-text publication is not yet available, were included in the quantitative synthesis to incorporate all available evidence. Finally, differences in follow-up duration across studies may have limited the ability to capture late adverse events or long-term efficacy trends, highlighting the need for extended follow-up data from ongoing large-scale RCT.

CONCLUSIONS

This meta-analysis indicates that DCB angioplasty may achieve clinical outcomes comparable to those of newer-generation DES for treatment of de novo coronary lesions, without evidence of ischemic superiority. A reduction in major bleeding was observed in studies adopting shorter dual antiplatelet therapy regimens, although this finding should be interpreted with caution. Overall, these findings may support the integration of DCB into routine daily clinical practice as a viable therapeutic strategy in selected clinical scenarios. However, large-scale randomized trials are still warranted to confirm their long- term safety and efficacy profile, as well as their potential superiority over DES.

FUNDING

None declared.

ETHICAL CONSIDERATIONS

Ethical approval was waived given the nature of the study.

STATEMENT ON THE USE OF ARTIFICIAL INTELLIGENCE

None declared.

AUTHORS’ CONTRIBUTIONS

R. Rinaldi, K. Bujak, G. Occhipinti, and C. Laudani contributed to conceptualization and design of the study, methodology, investigation, data curation, formal analysis, and participated in the drafting and review of the manuscript. S. Brugaletta contributed to the conceptualization and design of the study, methodology, investigation, data curation, project administration, supervision, and drafting, including critical review and editing of the manuscript. J. Sanz Sánchez, R.A. Montone, E. Nicolini, T. Piva, M. Gąsior, F. Ottani, F. Crea, S. Eccleshall, and M. Sabaté, contributed to drafting, review and editing of the manuscript. All authors have reviewed and approved the final version of the manuscript and agree to be accountable for all aspects of the work.

CONFLICTS OF INTEREST

F. Crea reports receiving speaker fees from Amgen, AstraZeneca, Abbott, Menarini, Chiesi, and Daiichi Sankyo. M. Sabaté reports receiving consultant fees from Abbott Vascular and iVascular. Other authors declared no conflicts of interest whatsoever.

SUPPLEMENTARY DATA

REFERENCES