Percutaneous treatment of the left main coronary artery in older adults. Impact of frailty on mid-term results

INTRODUCTION

Mitral regurgitation (MR) is a prevalent valvular heart disease associated with significant morbidity and mortality, particularly in patients with heart failure (HF).1 Traditional management strategies include optimal medical therapy to treat symptoms and surgery for definitive correction.2 However, current clinical practice guidelines only recommend mitral valve repair if the patient is undergoing another intervention such as coronary artery bypass graft or aortic valve replacement; nonetheless, many patients are at a high risk for surgery due to comorbid conditions, for this reason, alternative therapeutic options is required.3

Mitral transcatheter edge-to-edge repair (M-TEER) has emerged as a minimally invasive option for patients with symptomatic mitral regurgitation who are ineligible for surgery.4 While M-TEER has shown promising results, its comparative efficacy vs guideline- directed medical therapy (GDMT) is still a matter of discussion.5

This meta-analysis aims to assess the impact of M-TEER plus GDMT vs GDMT alone on major clinical outcomes in patients with secondary MR. The primary endpoint evaluated was HF-related hospitalization. Secondary endpoints included all-cause mortality, cardiac death, improvement in New York Heart Association (NYHA) functional class (FC), and the incidence rate of stroke and myocardial infarction. These endpoints were selected for their clinical relevance and potential to inform therapeutic decision-making in this high-risk patient population.

METHODS

We conducted this meta-analysis in full compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement guidelines.6 All the stages of this study were performed following the Cochrane Handbook for Systematic Reviews of Interventions, version 6.3.7 The protocol for this meta-analysis was registered prospectively in PROSPERO on 10 February 2025 with protocol ID CRD42025645047.

Search strategy

We conducted a systematic search across 3 electronic databases (PubMed, EMBASE, and COCHRANE) from inception until February 2025. Search terms included combinations of the following keywords: “transcatheter”, “secondary”, “mitral valve”, “replacement”, regurgitation”, and “insufficiency”. These keywords were combined using Boolean operators AND, OR. The reference lists of eligible studies and previous reviews were checked to identify additional valuable articles.

Criteria of the included studies

Studies were considered for inclusion in the meta-analysis based on the following criteria: a) randomized clinical trials (RCT) or observational cohort studies in Spanish or English that b) compared transcatheter mitral valve replacement vs optimal medical therapy in adult patients with mitral valve regurgitation due to secondary causes; and c) studies that reported outcomes of interest such as the index HF-related hospitalization, HF-related readmissions or cardiac death, and all-cause mortality.

Studies were excluded if they were non-original articles such as systematic reviews, letters, abstracts, meta-analyses, case reports, or case series. Furthermore, studies were excluded if mitral regurgitation was due to primary causes or if prior surgical repair had been performed.

Although observational cohort studies were eligible, we only identified 1 cohort study that did not meet the inclusion criteria during full-text screening. As a result, only RCTs were ultimately included in the meta-analysis.

Data extraction

To ensure accuracy, we used Zotero to eliminate duplicate references. We screened each paper based on title and abstract as a first step, followed by a full-text review as the second step. Two authors (D.A. Navarro Martínez, and D. Paulino-González) independently screened each paper, with any disagreements being resolved by a third author (A.L. García Loera). In addition, references of the included studies were reviewed and added if they met our eligibility criteria. Data extraction was conducted using Excel spreadsheets capturing the following information: a) baseline characteristics of the studied population, including baseline medication, echocardiographic baseline characteristics, and comorbidities; b) summary of the characteristics of the included studies; c) outcome measures; and d) quality assessment domains.

Primary and secondary endpoints

The primary endpoints established for this meta-analysis included: a) all-cause mortality (hazard ratio [HR]), defined as all-cause mortality, assessed using time-to-event analysis,8 and b) HF-related hospitalization, defined as hospital admission for worsening HF following the intervention (M-TEER or initiation of optimal medical therapy).9

Secondary endpoints included a) stroke, defined as an episode of neurological dysfunction caused by focal cerebral, spinal, or retinal infarction;10 and b) myocardial infarction, defined according to the Fourth Universal Definition.11

All endpoints were assessed as dichotomous categorical variables, which were reported in percentages. The risk ratio (RR) with its corresponding 95% confidence interval (95%CI) was calculated.

Assessment of heterogeneity

To assess heterogeneity, we used Cochrane’s Q-statistic with a significance level of P < .05. Additionally, the I²-statistic was used to quantify the proportion of variability due to heterogeneity, with values > 50% being considered indicative of high heterogeneity.12

Statistical analyses

To assess dichotomous data, we evaluated event frequencies and totals from each study group to calculate the RR and its 95%CI. Moreover, we obtained the HR and the 95%CI to calculate the standard error (SE).

The variables analyzed in this study were based on data reported in the original studies of the intention-to-treat principle. We implemented a random-effects model using the DerSimonian-Laird13 method to account for variability and allow comparison across studies. Given the limitations and strengths of this method, we conducted a sensitivity analysis using the Hartung-Knapp-Sidik-Jonkman method. Forest plots were utilized as a visual representation of the estimated outcomes.

Considering the differences in the populations included in the clinical trials, we conducted an additional exploratory analysis that focused on the RESHAPE-HF214 and COAPT15 trials for the primary endpoints by removing MITRA-FR16 from the analysis.

All statistical analyses, including the calculation of RR and SE, were conducted using RevMan V.5.4.1 software.

RESULTS

The initial database search yielded a total of 164 potentially relevant articles. After removing duplicates, a total of 129 articles finally remained for title and abstract screening. Following this initial screening, 8 articles were identified as potentially eligible for full-text review. Finally, after a detailed evaluation of the full texts under the predefined inclusion and exclusion criteria, 3 studies were included. A summary of the study selection process is shown in the PRISMA flowchart figure 1.

Figure 1. PRISMA 2020 flow diagram for new systematic reviews which included searches of databases and registers only.

Our analysis included 3 RCTs.14-16 We consulted the extended report of the 2-year outcomes of the MITRA-FR trial17 and 1 additional article on the RESAHPE-HF2 to obtain more data regarding hospitalization.18 All included studies compared the use of M-TEER plus GDMT vs GDMT alone. To standardize the outcomes, the median follow-up was set at 24 months; only the NYHA FC was evaluated with 1-year results. All 3 included studies used the MitraClip (Abbott, United States) device.

Clinical baseline characteristics of the patients

We obtained a total population of 1423 patients; among them 704 received M-TEER and 719, GDMT alone. In the RESHAPE-HF214 the device group showed the following characteristics: mean age was 70 years old; left ventricular ejection fraction (LVEF), 32%; median left ventricular end-diastolic volume (LVEDV), 200 mL; median effective regurgitation orifice (EROA), 0.23 cm²; median N-terminal pro-B-type natriuretic peptide (NT-proBNP), 2651; and brain natriuretic peptide (BNP), 556. In the COAPT15 trial, median age was 71 years old; LVEF, 31%; LVEDV, 194 mL; median EROA, 0.41 cm²; median NT-proBNP, 5174; and BNP, 1014. Finally in the MITRA-FR trial16, mean age was 71 years old; LVEF, 33%; LVEDV, 136.2 mL; median EROA, 0.31 cm²; median NT-proBNP, 3407; and BNP, 765. Regarding etiology, all trials enrolled mixed ischemic and non-ischemic etiology populations. Patient and study baseline characteristics, including comorbidities, drugs, and echocardiographic data, are shown in table 1, table 2, and table 3.

Table 1. Baseline characteristics of patients

Table 2. Summary of included studies

Table 3. Echocardiographic baseline characteristics

Risk of bias assessment

To evaluate the quality of the included randomized controlled trials, we used the Risk of Bias 2 (RoB2) tool from the Cochrane Handbook of Systematic Reviews of Interventions 6.3.7 This methodology allowed us to systematically assess the methodological quality of each study, thereby strengthening the validity of our findings.

Of the 3 studies, 1 had a low risk of bias,14 while the other 2 raised some concerns.15,16 The studies with some concerns were limited by factors in their methodologies, as they were open-label studies (figure 2).

Figure 2. Risk of bias for each included randomized clinical trial. The bibliographical references mentioned in this figure correspond to Stone et al.,14 Obadia et al.,15 and Anker et al.16.

Outcomes

HF-related hospitalization

The analysis of this outcome showed a significant reduction, with a RR of 0.71 (95%CI, 0.56-0.90; P = .004). However, substantial heterogeneity was observed, with an I² value of 79%. Considering the differences in the MITRA-FR study population, we conducted an exploratory analysis excluding this trial. Results still demonstrated a significant reduction in the risk of hospitalization, with a RR of 0.63 (95%CI, 0.55-0.72, P < .00001), along with a marked improvement in heterogeneity (I² = 0%). Of note, this finding is exploratory and should be interpreted with caution.

The analysis, including all studies, is shown in figure 3A, and the exploratory analyses are shown in figure 3B. Furthermore, we analyzed HR for this endpoint and, given the limited number of studies, we conducted a sensitivity analysis using the Hartung-Knapp-Sidik-Jonkman (HKSJ) method; all these analyses are provided in the supplementary data (figures S1-S4).

Figure 3. Forest plot of risk ratios (RR). Lines denote the 95% confidence intervals (95%CI) for each trial. A: forest plot of RR for HF related hospitalization. B: forest plot of exploratory RR for HF-related hospitalization. C: forest plot of RR for all-cause mortality. D: forest plot of exploratory RR for all-cause mortality. 95%CI, 95% confidence interval; GDMT, guideline directed medical therapy; M-TEER, mitral transcatheter edge-to-edge repair. The bibliographical references mentioned in this figure correspond to Stone et al.,14 Obadia et al.,15 and Anker et al.16.

All-cause mortality

The RR for all-cause mortality was 0.80 (95%CI, 0.63–1.02; P = .07). However, substantial heterogeneity was observed across the studies (I² = 56%). In the exploratory analysis, a significant reduction in mortality was found, with an RR of 0.71 (95%CI, 0.59–0.86; P = .0005) and no heterogeneity across the studies (I² = 0%). The analyses, including all studies, are shown in figure 3C, and the exploratory analysis in figure 3D.

Both the HR analysis and the sensitivity analysis are provided in the supplementary data (figures S5-S8).

Cardiac death

The RR for death from cardiovascular causes was 0.81 (95%CI, 0.62–1.06, P = .12), with low to moderate heterogeneity (I² = 48%). In the exploratory analysis, a significant reduction in cardiac death was observed, with an RR of 0.74 (95%CI, 0.55–1.00; P = .05) and low heterogeneity (I² = 41%). The analyses, including all studies, are shown in figure 4A, while the exploratory analysis, in figure 4B. The sensitivity analysis and HR results are provided in the supplementary data (figures S9-S12).

Figure 4. Forest plot of risk ratio (RR). A: forest plot of RR for cardiac death. B: forest plot of exploratory RR for cardiac death. C: forest plot of RR of NYHA FC I/II at 1 year. D: forest plot of RR for stroke. 95%CI, 95% confidence interval; GDMT, guideline directed medical therapy; M-TEER, mitral transcatheter edge-to-edge repair. The bibliographical references mentioned in this figure correspond to Stone et al.,14 Obadia et al.,15 and Anker et al16. Lines denote the 95%CI for each trial.

NYHA FC

In this analysis of the NYHA FC, we observed that patients undergoing M-TEER are more likely to be found in NYHA FC I/II at 12 months, with a RR 1.26 (95%CI, 1.06–1.50; P = .010), respectively. Of note, the high heterogeneity (I² = 72%). Furthermore, it is also essential to note that the NYHA FC is a subjective classification, which is why the findings of this outcome should be interpreted with caution. These results are shown in figure 4C.

Stroke

There were no statistical differences between M-TEER and optimal medical therapy regarding stroke, with a RR of 1.44 (95%CI, 0.76 - 2.73, P = .27) without any heterogeneity being reported across the studies (I² = 0%). These results are shown in figure 4D.

Myocardial Infarction

Regarding the risk of myocardial infarction, our analysis demonstrated no statistical difference between the M-TEER and optimal medical therapy groups (RR, 0.83; 95%CI, 0.43-1.61; P = .58). No heterogeneity among the studies was observed (I² = 0%); this finding is shown in supplementary data (figure S13).

Exploratory analysis by severity

We conducted an exploratory analysis stratified by the baseline grade of mitral regurgitation. Data on the composite endpoint of all-cause death or HF-related hospitalization were available according to MR grade. For patients with MR 3+, the RR was 0.75 (95%CI, 0.56-1.00; P = .05; I² = 12%). For those with severe MR 4+, data were available only from the RESHAPE-HF2 and COAPT trials, yielding a RR of 0.55 (95%CI, 0.42-0.73; P = .0001; I² = 0%). This finding is shown in the supplementary data (figure S14 to figure S15).

DISCUSSION

Our meta-analysis provides an evaluation of 3 major RCTs, COAPT15, MITRA-FR16, and RESHAPE-HF214, evaluating M-TEER plus GDMT vs GDMT alone in patients with secondary MR. In patients with persistent symptoms despite adequate GDMT and who do not meet the criteria for definitive surgical replacement, mitral M-TEER has emerged as a promising alternative. In this updated meta-analysis, no statistically significant effect on all-cause mortality was found; however, the marked between-trial heterogeneity suggests that M-TEER provides meaningful clinical benefit when used in appropriately selected patients.

Our study showed that heterogeneity of results was mainly driven by MITRA-FR. COAPT and RESHAPE-HF2 have multiple similar differences compared with MITRA-FR, as evidenced in trial cohort baseline characteristics, methods, and outcome directions. This is better portrayed by an exploratory analysis comparing COAPT and RESHAPE-HF2 results, showing a 37% reduction in the risk of HF-related hospitalization risk and a 32% reduction in cardiac death (figure 3). The overall neutral mortality rate resulting from our study may be driven by heterogeneity across trials rather than a lack of intrinsic therapeutic benefit.

Among the main differences across trials, the MITRA-FR trial had broader inclusion of patients with tricuspid regurgitation, advanced LV remodeling, greater dilation, and smaller EROA vs the other 2 trials. Another key source of heterogeneity was baseline MR severity. COAPT and RESHAPE-HF2 primarily enrolled patients with grade 3+ and 4+ MR, whereas MITRA-FR is only focused on grade 4+, which may contribute to the observed outcome differences. In our exploratory analysis by MR grade, data showed consistent trends favoring M-TEER; however, these findings should be interpreted with caution due to limited subgroup data.

As proposed by Paul et al.,19 one strategy to evaluate secondary MR is to consider the proportion between EROA and LVEDV. In the MITRA-FR trial, many patients had smaller EROA with markedly dilated ventricles, a phenotype in which GDMT may have more impact than valve proceduren. In the COAPT and RESHAPE-HF2 trials, a greater proportion of patients had large EROA relative to the LVEDV,20 making MR a primary driver of symptoms and outcomes, and, therefore, with potential for greater benefit from M-TEER.

In the trial-level subgroup analyses, the COAPT15 and RESHAPE-HF214 trials reported no significant interaction between treatment assignment and ischemic vs non-ischemic etiology, which indicates consistency of benefit across etiologies. Similarly, the MITRA-FR16 did not identify significant heterogeneity regarding etiology across prespecified subgroups. This suggests that ischemic vs non-ischemic alone should not be used to decide the treatment option in secondary MR. Instead, clinical decisions should prioritize other factors, such as the MR severity, the degree of LV dysfunction, symptom burden, and response to optimal medical therapy.21

Furthermore, differences between trials in procedural success are noteworthy, defined as achieving MR ≤ 2+. This was substantially lower in the MITRA-FR (75.6% MR ≤ 2+ at discharge) vs the COAPT (94.8% MR ≤ 2+ at 12 months) and the RESHAPE-HF2 (90.4% MR ≤ 2+ at 12 months). Multiple reasons could have influenced such differences; for instance, operator experience requirement in MITRA-FR (≥ 5 prior MitraClip cases) vs the high-volume and more experienced centers from the other trials. Similarly, post-approval data from the U.S. SSTS/ACC TVT Registry22 demonstrated > 90% MR reduction to ≤ 2+ and survival rates consistent with trial outcomes, underscoring the reproducibility of clinical benefit in experienced centers. Furthermore, device technology is a main contributor to these differences, from first-generation clips in MITRA-FR, to second-generation in COAPT, to the fourth-generation in RESHAPE-HF2 with independent leaflet grasping and wider arm options, potentially explaining discrepant clinical results regarding MR durability and outcomes. Lastly, GDMT implementation differed across trials. MITRA-FR was conducted before the widespread use of ARNI and SGLT2 inhibitors; COAPT was conducted before the adoption of SGLT2 inhibitors; and RESHAPE-HF2 reflects the contemporary use of quadruple therapy.

Despite the differences in patient phenotypes across the trials, in many developing countries, access to transcatheter valve procedures remains limited, primarily due to their high cost and the need for specialized infrastructure.23,24 The pronounced disparities in access to cutting-edge technologies, coupled with the centralization of these procedures in a few urban centers or high-specialty hospitals, a phenomenon observed even in high-income countries such as the United States, leave a substantial portion of the population without viable treatment options.25 Consequently, the most impactful and broadly deployable intervention in these regions remains rigorous GDMT optimization and provider education. Nevertheless, patient phenotyping should still be performed to identify those who may potentially have an outsized benefit from future M-TEER referrals.

By integrating trial-level population characteristics with clinical outcomes, our work bridges the gap between isolated trial findings and real-world patient selection, thus offering a potential framework for future prospective studies and for refining guideline criteria. While the results from our study must be interpreted with caution, they provide hypothesis-generating evidence supporting the concept that patient selection, particularly considering the balance between EROA and LVEDV and GDMT optimization, may be critical to optimizing the benefit of M-TEER in secondary MR. This approach moves beyond the broad application of current guideline recommendations and points toward a more individualized strategy in which anatomical and functional parameters guide intervention.

Limitations

The primary limitation of this study lies in the heterogeneity of the populations enrolled in the randomized controlled trials, as evidenced by the I2 observed in the analyses, which may influence the overall results. Second, differences in MR severity across trials represent a key limitation. While the COAPT and RESHAPE-HF2 trials mainly included patients with MR grade 3+ or 4, MITRA-FR enrolled a more severe grade, which may partly explain divergent results. Lastly, an individual patient-level meta-analysis could not be conducted due to lack of data; this level of analysis would further increase statistical power, especially in subgroup analyses, enhancing the robustness and generalizability of the findings.

CONCLUSIONS

In this meta-analysis, M-TEER plus GDMT shows a lower risk of HF-related hospitalization vs GDMT alone. We did not find any differences in the risk of all-cause mortality, cardiac death, stroke, or myocardial infarction.

FUNDING

None declared.

ETHICAL CONSIDERATIONS

This meta-analysis was performed using data from previously published studies. As it is based entirely on secondary data, no new data were collected from human or animal participants; on the other hand, the use of SAGER guidelines was not applicable in this study. All included studies were approved from the relevant center ethics committees. The authors confirm that all data utilized were publicly accessible, and no confidential information was used without proper authorization.

STATEMENT ON THE USE OF ARTIFICIAL INTELLIGENCE

During the preparation of this work, the authors used ChatGPT 4o to review the document’s syntax and grammar. After using this tool/service, the authors reviewed and edited the content as needed and take full responsibility for the content of the published article.

AUTHORS’ CONTRIBUTIONS

D. Paulino-González: conceptualization; formal analysis, writing, review, and editing. A.L. García-Loera: methodology, investigation, writing, review, and editing. D.A. Navarro-Martínez: methodology, formal analysis. M.A. Pardiño-Vega: writing, review, and editing, supervision. K.P. Zúñiga-Montaño: investigation, writing, review, and editing.

CONFLICTS OF INTEREST

None declared.

SUPPLEMENTARY DATA

REFERENCES

INTRODUCTION

Following percutaneous coronary intervention (PCI) in patients with acute coronary syndrome (ACS), a 12-month regimen of dual antiplatelet therapy with a P2Y₁₂ receptor inhibitor and acetylsalicylic acid is recommended, regardless of the type of stent implanted, except when contraindicated.1 Although prasugrel and ticagrelor are preferred over clopidogrel in this setting, there is ongoing debate regarding the potency and duration of dual antiplatelet therapy. This controversy stems from the fact that most patients concurrently face 2 opposing and potentially fatal risks—ischemic and hemorrhagic—which must be carefully balanced on an individual basis.

The introduction of stents with reduced thrombogenicity, together with evidence that thrombotic risk is highest during the first few months after PCI while hemorrhagic risk remains relatively constant throughout time, has led to research efforts focused on minimizing bleeding complications. These strategies include shortening dual antiplatelet therapy, using P2Y₁₂ inhibitors as monotherapy, and implementing de-escalation strategies.2,3

De-escalation consists of switching from prasugrel or ticagrelor to clopidogrel and can be guided (using genetic or platelet function testing) or unguided. Because this strategy may increase ischemic events, it is not recommended within the first month after PCI.1

In the TOPIC trial,4 the unguided de-escalation strategy initiated 1 month after ACS significantly reduced hemorrhagic events (Bleeding Academic Research Consortium [BARC] grade ≥ 2 bleeding events) at 1 year without increasing the ischemic ones. In the TROPICAL-ACS trial,5 the platelet function testing–guided de-escalation from prasugrel to clopidogrel 2 weeks after revascularization was noninferior to standard therapy, showing a trend toward fewer hemorrhages at 12 months and a similar rate of thrombotic events.1,2,6 In the TALOS-AMI trial,7 12-month event rates were lower, primarily because of fewer hemorrhagic events among patients who underwent unguided de-escalation 1 month after ACS. Table 1 summarizes these studies.

Table 1. De-escalation clinical trials in patients with acute coronary syndrome

After the positive results of the TOPIC trial, the VerifyNow to optimise platelet inhibition in coronary acute syndrome (EPIC17-VERONICA) trial (ClinicalTrials.gov: NCT04654052) aims to further refine this strategy by only applying de-escalation to patients with excessive antiplatelet effects from prasugrel or ticagrelor after the first month who are at theoretical risk of hemorrhage based on the VerifyNow platelet aggregation test (Werfen, Spain). Thus, patients demonstrating an adequate pharmacologic response will continue prasugrel or ticagrelor therapy for 1 year, whereas those with very low platelet reactivity after a 1-month regimen of dual antiplatelet therapy with these agents constitute the target population of this study.

METHODS

Design

We are conducting a multicenter, prospective, randomized clinical trial at 16 Spanish centers. Based on the results of the platelet aggregation test for P2Y₁₂ inhibition (platelet reactivity units [PRU]) using the VerifyNow system, patients with very low platelet reactivity (PRU ≤ 30) are randomized in a 1:1 ratio to either continue treatment with ticagrelor or prasugrel, or to de-escalate to clopidogrel. Patients with PRU > 30 are not randomized. The study flowchart is shown in figure 1.

Figure 1. Study flowchart. AAS, acetylsalicylic acid; PRU, platelet reactivity units.

The study is being conducted in full compliance with the principles outlined in the Declaration of Helsinki and has been approved by the central ethics committee (Comité del Bierzo, León, Spain) and endorsed by the ethics committees of all participant centers. The appendix lists the participant centers and principal investigators.

The study sponsor (Fundación para la Educación en Procedimientos de Intervencionismo en Cardiología [EPIC]) is fully responsible, together with the principal investigators, for data management and confidentiality.

Population

Inclusion and exclusion criteria

Table 2 summarizes the inclusion and exclusion criteria. Briefly, all patients with ACS undergoing PCI with a sirolimus-eluting stent and a bioresorbable polymer during hospitalization and discharged on dual antiplatelet therapy with acetylsalicylic acid and ticagrelor or prasugrel are eligible for inclusion.

Table 2. Inclusion and exclusion criteria

Written informed consent must be obtained before the platelet aggregation tes is performed.

Study protocol and randomization

Eligible patients are scheduled for P2Y₁₂ receptor inhibition testing with the VerifyNow system between 30 and 40 days after hospital discharge. Measurements are obtained at least 6 hours after the administration of the last P2Y₁₂ inhibitor dose. Patients with PRU ≤ 30 (very low platelet reactivity) are randomized in a 1:1 ratio using an electronic system to either continue their current treatment or de-escalate to clopidogrel, 75 mg once daily. De-escalation is preceded by a loading dose of 600 mg administered 24 hours after the last dose of ticagrelor or 75 mg 24 hours after the last dose of prasugrel, in accordance with the 2017 European Society of Cardiology clinical practice guidelines.8

The remaining patients with PRU > 30 are not randomized, and their dual antiplatelet therapy remains unchanged from discharge.

Clinical follow-up

Patients in the 2 randomized groups undergo telephone follow-up to monitor clinical events at 2, 5, 8, and 11 months after enrollment, corresponding to 3, 6, 9, and 12 months after hospital discharge.

For patients with PRU > 30 on the 1-month VerifyNow platelet aggregation test who are not randomized, only baseline characteristics are recorded, and no further follow-up is conducted.

Protocol of the VerifyNow platelet aggregation test

The VerifyNow system determines platelet activity by measuring in vitro aggregation in a blood sample exposed to specific agonists. This optical detection instrument (figure 2), which operates on a turbidimetric principle, uses single-use cartridges. In this study, PRUTest-specific kits are employed. (Werfen, Spain) to assess platelet aggregation while on P2Y₁₂ receptor inhibitor therapy (ticagrelor, prasugrel, and clopidogrel). Each PRUTest kit contains lyophilized microbeads coated with fibrinogen, platelet activators, and a buffered solution. The test is based on the ability of activated platelets to bind fibrinogen-coated microbeads. Light transmission increases as activated platelets bind to and aggregate with the fibrinogen-coated microspheres. The kit measures this change in the optical signal and reports the results in PRU units (figure 3).

Figure 2. VerifyNow system. Reproduced with permission from Werfen.

Figure 3. Performance of the VerifyNow system based on light transmission aggregometry. Light transmission increases as activated platelets bind and aggregate to the fibrinogen-coated microbeads in the kit. Therefore, high light transmission (corresponding to elevated platelet reactivity unit [PRU] values) indicates normal platelet function, whereas low light transmission (decreased PRU values) reflects platelet inhibition induced by the tested drugs.

An antiplatelet effect of the drug is considered present with PRU ≤ 180 (figure 4). Only patients with PRU ≤ 30 are randomized, as these are considered to have very low platelet reactivity while on antiplatelet therapy.

Figure 4. Reference levels for platelet reactivity units (PRU). 95%CI, 95% confidence interval.

Endpoints

The primary endpoint of the study is to compare the efficacy of de-escalation from ticagrelor or prasugrel to clopidogrel in patients undergoing PCI in the ACS setting, using the VerifyNow platelet aggregation test vs standard dual antiplatelet therapy at the 1-year follow-up. The rate of net adverse cardiovascular events is the primary endpoint of the study, defined as a composite of cardiac death, nonfatal myocardial infarction, nonfatal stroke, and hemorrhage (defined as Bleeding Academic Research Consortium [BARC] grade ≥ 2 bleeding events). The BARC scale is shown in table S1.

Furthermore, the study aims to compare several secondary endpoints (table 3), such as the occurrence of ischemic events during follow-up: cardiac death and all-cause mortality, acute myocardial infarction, stroke, stent thrombosis, and need for emergency revascularization. Moreover, the hemorrhage rate (defined as BARC grade ≥ 2 bleeding events) will be compared. The definitions of all study endpoints are shown in table S2.

Table 3. Endpoints of the study

Statistics

Sample size calculation

Sample size was calculated for the randomized clinical trial cohort. The total number of patients (including those not randomized with PRU > 30) will depend on the total required to reach the estimated sample size for the randomized clinical trial.

We estimate a smaller difference in event rates across the groups than that observed in the TOPIC trial,4 specifically, 14% in the de-escalation group vs 22% in the standard therapy group. Assuming a significance level of 0.05, a power of 80%, a 2-tailed P-value and a 10% loss to follow-up, a total of 634 randomized patients (317 per group) will be required.

Statistical analysis plan

Quantitative variables will be expressed as mean and standard deviation if normally distributed, or as median and interquartile range otherwise. Categorical variables will be expressed as absolute values and percentages. Study data will be analyzed using one-way analysis of variance (ANOVA) for continuous variables, and Fisher’s exact or chi-square tests for categorical variables, as appropriate. Nonparametric tests will be used for variables that are not normally distributed or cannot be normalized. For the main outcome measure, Kaplan-Meier survival curves with log-rank statistics will be presented for prespecified criteria, and multivariable Cox regression will be performed to adjust for known risk factors and potential confounders. Hazard ratios and 95% confidence intervals will be reported for all statistically significant variables.

Intention-to-treat (according to randomization assignment) and per-protocol analyses (in case of crossover) will be conducted. The former will serve as the study primary analysis.

DISCUSSION

The EPIC17-VERONICA trial aims to demonstrate the efficacy of a VerifyNow platelet aggregation test-guided de-escalation strategy in reducing hemorrhagic events without increasing ischemic events in patients with ACS who have undergone percutaneous revascularization and exhibit very low platelet reactivity after the first month of treatment with prasugrel or ticagrelor.

The initial lack of expected results from platelet function testing to identify patients at risk for thrombotic events while on clopidogrel in the GRAVITAS,9 TRIGGER-PCI,10 and ARCTIC11 trials relegated its use to a class IIb recommendation in the European Society of Cardiology antiplatelet guidelines for determining the optimal timing of cardiac surgery after ACS.8 However, the 1-year results of the large-scale multicenter ADAPT-DES trial12 with 8500 PCI patients demonstrated that platelet reactivity assessed with the VerifyNow platelet aggregation test is an independent predictor of bleeding events.

In the TOPIC4 and TALOS-AMI7 trials, the unguided de-escalation strategy significantly reduced bleeding events without increasing ischemic events. In the TROPICAL-ACS5 trial, this platelet aggregation test–guided de-escalation strategy showed a trend toward fewer hemorrhages, with a similar rate of thrombotic complications.

The EPIC17-VERONICA study further seeks to improve the application of this de-escalation strategy by using the VerifyNow platelet aggregation test to identify patients with very low platelet reactivity (PRU ≤ 30) as those most likely to benefit from de-escalation.

CONCLUSIONS

The EPIC17-VERONICA trial has been designed to investigate the efficacy of de-escalating from the most potent antiplatelet agents (ticagrelor and prasugrel) to clopidogrel after the first month of therapy in patients with ACS and very low platelet reactivity, aiming to reduce bleeding events without increasing ischemic complications. Furthermore, it will provide evidence on the clinical utility of the VerifyNow platelet aggregation test for patient selection.

FUNDING

None declared.

ETHICAL CONSIDERATIONS

The study is being conducted in full compliance with the principles outlined in the Declaration of Helsinki on clinical research and has been approved by the central ethics committee (Comité del Bierzo, León, Spain) and endorsed by the ethics committees of all participant centers. Written informed consent is required prior to performing ant platelet aggregation measurements. Sex and gender bias considerations have been addressed.

STATEMENT ON THE USE OF ARTIFICIAL INTELLIGENCE

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

AUTHORS’ CONTRIBUTIONS

C. Garilleti Cámara and I. Lozano Martínez-Luengas drafted the manuscript; the remaining authors critically revised the document and approved the final version.

CONFLICTS OF INTEREST

J.M. de la Torre Hernández is Editor-in-Chief of REC: Interventional Cardiology; A. Pérez de Prado is Associate Editor of REC: Interventional Cardiology. In both cases, the journal’s editorial procedure to ensure impartial handling of the manuscript has been followed. The remaining authors declared no conflicts of interest whatsoever.

SUPPLEMENTARY DATA

REFERENCES

INTRODUCTION

Calcified coronary nodules (CN) represent the most complex type of calcified lesion for percutaneous coronary intervention (PCI), as they are associated with worse angiographic and clinical outcomes after drug-eluting stent (DES) implantation.1-8

Intravascular lithotripsy (IVL) has shown favorable results in this context.9 However, stent implantation after IVL may not always be the best treatment option due to suboptimal stent expansion and severe malapposition in a non-negligible percentage of patients which, along with possible nodule protrusion through the stent struts, may be associated with an increased need for new target lesion revascularization (TLR), and a higher rate of major adverse cardiovascular events (MACE).10-12

Drug-eluting balloons (DEB) have demonstrated to be a safe and effective alternative to DES in various settings, especially in those in which stenting is associated with worse outcomes, such as small vessel disease and in-stent restenosis.13 Therefore, their use has increased exponentially in recent years and has expanded to other lesion types.14

In the specific setting of calcified lesions, there are some data on the safety and efficacy profile of DEB after an adequate plaque modification.15-19 Moreover, in this setting, DEB have shown similar clinical outcomes with favorable late lumen loss rate compared with DES.20-23

Despite the increasing use of DEB in calcified lesions, evidence on the safety and efficacy profile of CN treatment is lacking. In this setting, where the risj of suboptimal stent expansion and apposition—and the consequent likelihood of MACE— is higher,24 a leave-nothing-behind strategy using DEB following optimal plaque modification technique may be a more appealing approach.Therefore, our aim is to compare the safety and efficacy profile of the use of DEB or DES after IVL in CN within the context of a randomized controlled trial.

METHODS

Patients and study design

The DEBSCAN-IVL trial is an investigator-initiated, multicenter, open-label, prospective, randomized, controlled clinical trial including 10 high-volume centers.

Patients will be randomized to receive a DEB or a DES after optimal treatment with IVL if they meet all the inclusion criteria and have no exclusion criteria. Inclusion criteria are age ≥ 18 years with a clinical indication for PCI (presenting with chronic or acute coronary syndromes) in a CN-induced de novo severe coronary lesion (confirmed via intracoronary imaging) in vessels with a reference diameter between 2.5 mm and 4.0 mm. Patients who meet at least 1 of the following conditions will be excluded: inability to provide oral and written informed consent or unwillingness to return for systematic angiographic follow-up; pregnant or breastfeeding patients; cardiogenic shock or cardiac arrest at the time of the index procedure; inability to maintain dual antiplatelet therapy for at least 1 month; life expectancy < 1 year; index lesion located at the left main coronary artery or in an aorto-ostial location; target lesion previously treated with stents or DEB or with high thrombus burden at the time of PCI (Thrombolysis In Myocardial Infarction [TIMI] thrombus grade ≥ 3).

Patients who meet all the inclusion criteria and none of the exclusion criteria will be treated with IVL and randomized to receive final therapy with DEB or DES. Randomization will occur via a web-based system. The complete inclusion and exclusion criteria are shown in table 1, and the study flowchart in figure 1.

Table 1. Inclusion and exclusion criteria

Figure 1. Central illustration. Study design flowchart. CN, calcified coronary nodule; DEB, drug-eluting balloons; DES, drug-eluting stents; IVL, intravascular lithotripsy; OCT, optical coherence tomography; PCI, percutaneous coronary intervention.

Primary and secondary endpoints

The endpoint of this study is to evaluate and compare the safety and efficacy profile of DEB or DES as final treatment strategies for CN previously modified by IVL.

Co-primary endpoints will be the late lumen loss (LLL) and net luminal gain at 9 ± 1 months of angiographic follow-up, as assessed by an independent core laboratory, with a non-inferiority hypothesis between the 2 groups. LLL is defined as the difference between postoperative and follow-up minimal lumen diameter, whereas net gain is defined as the difference between follow-up and preoperative minimal lumen diameter, according to the latest Drug Coated Balloon Academic Research Consortium Consensus Document.25

Secondary endpoints of the study will include procedural, angiographic and clinical outcomes. Procedural endpoints will include the rate of crossover between treatment groups, angiographic success (defined as final TIMI grade-3 flow and a residual final percent diameter stenosis < 30% in the DEB group or < 20% in the DES group), device success (defined as angiographic success without crossover between treatment group), procedural success (defined as angiographic success without the occurrence of severe procedural complications, including cardiac death, target vessel perioperative myocardial infarction [MI], need for new clinically driven TLR, stent thrombosis [ST], stroke, flow-limiting dissection or vessel perforation). Angiographic endpoints will include the minimal lumen diameter measured immediately after the intervention and at the time of angiographic follow-up, the residual percent diameter stenosis at both timeframes, and the rate of binary restenosis, defined as a luminal diameter reduction o≥ 50% during follow-up.25 Secondary endpoints will include procedural adverse events (such as dissection, perforation, acute vessel occlusion, slow flow or no-reflow, and intraoperative thrombosis), major hemorrhagic events (classified as Bleeding Academic Research Consortium [BARC] type ≥ 3),26 and hemodynamic instability (requiring unplanned administration of vasopressors, inotropes, or ventricular support devices), cardiac death, target lesion-related MI (TL-MI), need for TLR, and ST, and MACE (defined as a composite of cardiac death, TL-MI, and TLR). TLR and ST are defined according to the Academic Research Consortium criteria.27 MACE and its components will be assessed during the index hospitalization and at 6-month, 1-year, and 2-year follow-up visits. Detailed endpoints definitions are shown in appendix S1.

Primary outcome assessment will be conducted by a central independent core laboratory. All medical data will be anonymized and stored, and confidentiality will be protected at any time in full compliance with the current legislation. The clinical events committee (CEC) and the independent core laboratory will be blinded to the treatment group. Secondary outcomes will be assessed via centralized angiographic analysis and structured clinical follow-up, either in person or via telephone, at scheduled time points.

Devices

• – IVL: Shockwave Balloon (Shockwave Medical, United States).
• – Optical coherence tomography (OCT) or intracoronary ultrasound (IVUS) system, based on availability at each participating center.
• – DEB: paclitaxel-eluting balloon (Pantera Lux, Biotronik, Switzerland)
• – DES: new-generation zotarolimus eluting stent (Onyx Frontier, Medtronic, United States).

Procedure

When a CN is suspected on coronary angiography, intracoronary imaging—preferably OCT, with IVUS as an alternative—will be performed to confirm the diagnosis. After confirmation of a CN in the target lesion, patients will be randomized on a 1:1 ratio to receive a DEB or a DES. Randomization will be stratified to ensure a balanced distribution of eruptive and non-eruptive nodules across both treatment groups. A CN (figure 2) will be defined as a calcified segment with an accumulation of protruding nodular calcification (small calcium deposits) with disruption of the fibrous cap (eruptive CN) or an intact thick fibrous cap (non-eruptive CN).28-30

Figure 2. Calcified nodule appearance on angiography (A), optical coherence tomography (eruptive [B] and non-eruptive [C]) and intravascular ultrasound (D).

All patients will be treated with IVL, using a balloon sized 1:1 to the vessel reference diameter. A minimum of 80 pulses per lesion is recommended. If the IVL balloon cannot cross the lesion, predilation with smaller balloons is permitted. Additionally, the use of adjuvant techniques such as rotational atherectomy or excimer laser coronary atherectomy will be allowed only when deemed necessary to facilitate IVL balloon crossing. Postdilation with a non-compliant balloon after IVL is recommended before proceeding with the final assigned treatment modality.

Once optimal lesion preparation has been achieved, defined as > 80% balloon expansion in 2 orthogonal projections with a balloon sized 1:1 to the vessel, patients will receive a DEB or a DES, according to their initial randomization. If a patient randomized to the DEB group experiences a flow-limiting dissection or exhibits a percent diameter stenosis > 50%, conversion to DES implantation will be permitted at the operator’s discretion. Similarly, any crossover from DES to DEB will be documented, along with the reasons for these procedural decisions.

It is recommended that the DEB reach the target lesion within 2 minutes, as drug loss may occur during transit.13 Thus, operators need to anticipate difficulties in reaching the target lesion (proximal coronary disease or tortuosity) and ensure optimal support prior to using the DEB. If difficulties in reaching the target lesion are anticipated, the use of guide extension catheters is recommended. The recommended DEB inflation time is 60 seconds.

The PCI will be performed according to current European Society of Cardiology (ESC) guidelines, including perio- and postoperative antithrombotic management.31,32 Patients should ideally receive dual antiplatelet therapy at least 2 to 4 hours prior to the PCI to ensure optimal platelet inhibition. In cases where this is not feasible, administration of IV antiplatelet agents, such as acetylsalicylic acid with or without cangrelor, immediately before the procedure is recommended.

Intracoronary imaging with either OCT or IVUS (the same imaging modality that was initially used) is recommended at the end of the procedure.

Angiographic analysis

Quantitative coronary imaging and intracoronary analysis of baseline and follow-up angiographies will be conducted by an independent central laboratory (Barcicore, Spain). At least 2 well-selected orthogonal views—free of foreshortening and side-branch overlap—focused on the target lesion are required after intracoronary nitroglycerine administration. These views should be obtained before treatment, after the intervention, and during follow-up angiography to ensure consistent angulation and enable accurate, reproducible measurements.

Follow-up

Post-PCI antithrombotic therapy will abide by the latest ESC clinical practice guidelines, considering the individual ischemic and bleeding risk profile of each patient.31,32 Regardless of the assigned treatment group (DEB or DES), a 6-month regimen of dual antiplatelet therapy (aspirin and clopidogrel) is recommended in patients with stable coronary artery disease, and a 12-month regimen of dual antiplatelet therapy (preferably using prasugrel or ticagrelor as a P2Y₁₂ inhibitor) in patients with acute coronary syndrome. For patients requiring chronic oral anticoagulation, the choice and duration of antithrombotic therapy will follow current guideline recommendations, with triple therapy (oral anticoagulant + aspirin + clopidogrel) limited to 1 month, whenever feasible. Electrocardiogram and troponin assessment will be performed 24 hours after the PCI. All patients will be discharged with a scheduled angiographic follow-up at 9 ± 1 months. OCT is recommended during this follow-up, especially if angiography suggests progression of coronary artery disease in the target lesion. In cases where angiography or intracoronary imaging indicates disease progression, but the percent diameter stenosis is < 90%, revascularization should be guided by ischemia and confirmed with a pressure guidewire. Clinical follow-up visits are scheduled at 12 and 24 months. Schedule of visits and data assessment throughout the study are shown in table S1.

Statistical analysis

The primary endpoint analysis will be performed by lesion and by intention-to-treat with a 1-sided Student t test with an alfa of 0.05 between the DES and the DEB group. A per-protocol analysis, including crossover cases, will also be conducted for sensitivity purposes. If the hypothesis of non-inferiority is confirmed, a superiority 2-sided analysis will be performed. Clinical endpoints will be analyzed on a per-patient basis.

Quantitative variables will be expressed as mean ± standard deviation if normally distributed, and as median with minimum and maximum values if they do not follow a normal distribution. Normality will be assessed using the Kolmogorov-Smirnov test. Qualitative variables will be described by their absolute values and frequencies, and will be expressed as absolute counts and percentages. A P < .05 will be considered statistically significant, and 95% confidence intervals (95%CI) will be reported for all main analyses. For comparisons of continuous variables between the 2 groups, the Student t test will be used if normality is confirmed, or the Mann-Whitney U test if non-parametric. For comparisons across > 2 groups, the ANOVA test or the Kruskal-Wallis test will be applied, as appropriate. Associations across categorical variables will be analyzed using the chi-square test or Fisher’s exact test when expected frequencies are small. Correlations between continuous variables will be explored using Pearson’s or Spearman’s correlation coefficient, depending on their distribution.

A multivariate analysis will be conducted using Cox proportional hazards regression with forward stepwise selection, including variables that are significantly associated with outcomes (or show a trend) in the univariate analysis. Kaplan-Meier curves will be generated for event-free survival, and differences will be assessed using the log-rank test.

Prespecified subgroup analysis

Subgroup analysis will be performed according to the following prespecified categories: type of calcified nodule (eruptive vs non-eruptive), age (< 75 vs ≥ 75 years), sex (male vs female), presence of diabetes mellitus (yes vs no), location of the calcified nodule within a true bifurcation lesion involving a side branch ≥ 2.5 mm (yes vs no), and clinical presentation (acute coronary syndrome vs chronic coronary syndrome). In addition, a prespecified OCT subgroup analysis will be performed in patients with available OCT imaging at both the end of the procedure and follow, including assessments of minimal lumen area (or minimal stent area in stented segments) and minimal lumen diameter.

Sample size calculation

The hypothesis is that DEB-PCI for CN is not inferior to state-of-the-art DES-PCI in terms of LLL and net luminal gain at the lesion. The sample size calculation was based on an expected LLL of 0.20 mm in the DES group, with a non-inferiority margin (delta) of 0.30 mm, a significance level (alpha) of 5%, and a statistical power of 80%. The estimate of LLL in the control group was derived from previous studies evaluating the same DES platform.33-35 Assuming a 20% attrition rate for angiographic follow-up, 64 patients per group (128 patients in total) will be required to provide adequate statistical power. The study is not powered for clinical endpoints, which will be considered exploratory and hypothesis-generating.

Organization and ethical concerns

The study protocol has been approved by the local ethics committees of all participant centers. Written informed consent will be obtained from all patients prior to enrollment. The DEBSCAN-IVL trial is an investigator-initiated study conducted in full compliance with Good Clinical Practice guidelines applicable to interventional and epidemiological research. The rights, safety, and well-being of all participants will be protected full compliance with the principles set forth in the Declaration of Helsinki, applicable EU legislation, and local legal requirements. Participant data will be handled confidentially and anonymously. The trial is registered at ClinicalTrials.gov (NCT06657833). The sponsor of the study is Fundación EPIC. The study is supported by unrestricted research grants from Fundación EPIC, Shockwave Medical, Biotronik, and Medtronic.

The steering committee serves as the primary decision-making body of the trial and bears full responsibility for its scientific and clinical conduct. A clinical events committee (CEC), composed of independent interventional cardiologists not participating in the study and blinded to treatment allocation, will adjudicate all clinical events and endpoints. The CEC will operate according to pre-specified definitions outlined in the study protocol and will remain blinded to the overall trial outcomes.

DISCUSSION

CN represent the most complex type of calcified lesion for PCI, as they are associated with the worst angiographic and clinical outcomes after DES implantation.1-8 Three main factors may contribute to these unfavorable results: the nature of the nodule per se, the plaque modification technique used, and the final revascularization strategy (DES or DEB). Although our understanding of the origin and behavior of calcified nodules has grown, it remains unclear which lesions are likely to respond favorably to PCI, and which are not. Eruptive CN, for instance, may be more amenable to initial modification, yet paradoxically, they have also been associated with higher rates of adverse clinical events during follow-up.29,36

Regarding plaque modification techniques, current evidence is limited. Rotational atherectomy (RA), while commonly used, is constrained by wire bias and frequently requires large burr sizes.2 Although orbital atherectomy might overcome some of these limitations, randomized data comparing it with other advanced plaque modification techniques are lacking.37 Balloon-based techniques, in contrast, may fail to cross severely stenotic nodular lesions but have the advantage of avoiding the wire bias inherent to atherectomy.

However, conventional or scoring/cutting balloons often prove insufficient to fully modify the depth of nodular calcium, and very high-pressure special balloons carry the risk of overstretching the usually normal opposite vessel wall causing perforation. In this context, IVL has emerged as a promising alternative, offering the most robust evidence to date for nodular plaque modification.29,38

Traditionally, stent implantation has been the standard definitive treatment for CN.23 However, stenting in nodular lesions frequently leads to suboptimal expansion and incomplete apposition, particularly at the shoulders of the nodule. Moreover, In these patients, TLR is often driven not by classic in-stent restenosis, but by late protrusion of the calcified nodule through the stent struts.10,11,39 These limitations have generated interest in a “leave nothing behind” strategy after effective plaque modification.

DEB have demonstrated to be safe and effective in various settings, particularly small vessel disease and in-stent restenosis, where DES implantation may be less favorable.13 Therefore, their use has grown significantly in recent years.14 In the context of calcified lesions, there are concerns that adequate drug-uptake may be compromised, but preliminary evidence suggests DEB may offer good outcomes after adequate plaque preparation.15-17 For instance, Ito et al.18 evaluated a total of 81 patients with de novo lesions treated with DEB, including 46 with calcified lesions. While LLL and restenosis appeared slightly higher in the calcified group, these differences were not statistically significant and did not translate into worse clinical outcomes at 2 years. Notably, 82% of these lesions were pre-treated with RA. Similarly, Nagai et al. reported a TLR rate of 16.3% in 190 severely calcified lesions treated with RA followed by DEB.19 Rissanen et al. found MACE rates of 14% and 20% at 12 and 24 months, respectively, in 82 complex de novo calcified lesions treated with DEB after RA and balloon predilation, with very low rates of clinically driven TLR.20 Furthermore, favorable findings have been reported by Shiraishi et al., including a subset of calcified nodules.16

Comparative studies have further explored DEB vs DES in calcified lesions. Ueno et al.21 conducted a single-center cohort study comparing the clinical outcomes of 166 severe calcified lesions treated with either DEB or DES after RA at a median follow-up of 3 years. The TLR rates were similar across the groups (15.6% vs 16.3%; P = .99), while LLL was significantly lower in the DEB group (0.09 mm vs 0.52 mm; P =.009). Iwasaki et al.22 compared 194 patients with de novo calcified lesions in non-small vessels the RA + DEB vs RA + DES strategies. There were no significant differences at 1 year in terms of MACE, cardiac death, myocardial infarction, TLR or hemorrhage.

Despite this data on the performance of DEB in calcified lesions, evidence on the safety and efficacy profile in the CN setting is lacking. However, given the high likelihood of suboptimal stent expansion and malapposition in this setting, which may lead to increased MACE risk,24 a metal-free strategy using DEB following optimal plaque modification seems to be an attractive and feasible approach.

Intracoronary imaging-guided PCI has been consistently associated with improved procedural outcomes and a reduction in major adverse cardiovascular events, including mortality, particularly in complex lesions.40 Intracoronary imaging plays a pivotal role in this context. Compared with conventional angiography, it provides a far more accurate assessment of coronary disease severity and plaque morphology.1 This is particularly relevant in calcified and complex lesions, where procedural planning and outcomes are significantly impacted by the detailed anatomical insights obtained. OCT, in particular, offers superior spatial resolution compared to IVUS, allowing for precise quantification of the calcium burden.28,41

In the case of CN, OCT enables accurate assessment of the plaque substrate and procedural results, including stent expansion and apposition, or in DEB-treated lesions, the extent of plaque modification.

The DEBSCAN-IVL trial will be comparing the safety and efficacy profile of DEB vs DES after lesion preparation with IVL in patients with CN, assessing both angiographic and clinical outcomes. Moreover, the trial will provide valuable information on the underlying plaque morphology and the response to different PCI strategies following the systematic use of intracoronary imaging. The central hypothesis of the study is that a DEB strategy, after IVL-based plaque modification in calcified nodules, is not inferior to DES implantation in terms of LLL and net gain, while potentially reducing the risk of long-term adverse events through improved biocompatibility and vessel healing. In addition, the analysis will be stratified according to nodule morphology, specifically differentiating eruptive vs non-eruptive CN, 2 entities that are thought to have distinct biological behavior and potentially different response to plaque modification and PCI.6,7,29,36 This stratified analysis may provide novel insights into the prognostic and therapeutic implications of nodule subtype and guide future individualized interventional strategies.

CONCLUSIONS

The DEBSCAN-IVL trial is an investigator-initiated, multicenter, open-label, prospective, randomized, controlled clinical trial designed to compare the safety and efficacy profile of the use of DEB or DES after IVL in CN. The co-primary endpoints are LLL and net gain at 9 ± 1 months of angiographic follow-up. The findings are expected to inform clinical decision-making and support a more individualized approach on the management of this specific type of calcified coronary disease.

DATA AVAILABILITY

This manuscript refers to the protocol of a study, therefore there is not available data related to this manuscript.

FUNDING

The DEBSCAN-IVL study was supported by non-restricted grants from Shockwave, Biotronik and Medtronic.

ETHICAL CONSIDERATIONS

The study was conducted in full compliance with the principles set forth in the Declaration of Helsinki. Institutional Ethics Committee approval was obtained, and all participants gave their written informed consent prior to enrollment. The confidentiality and anonymity of participants were strictly preserved throughout the study. Sex and gender considerations were addressed following the recommendations of the SAGER guidelines to ensure accurate and equitable reporting.

STATEMENT ON THE USE OF ARTIFICIAL INTELLIGENCE

Artificial intelligence assisted technologies were used exclusively to support language editing and improvement of style. No artificial intelligence tools were employed to generate, analyze, or interpret the data. The authors take full responsibility for the integrity, accuracy, and originality of the manuscript content.

AUTHORS’ CONTRIBUTIONS

A. Jurado-Román, M. Basile and R. Moreno drafted the manuscript. The remaining authors performed a critical review, and all authors approved the final version for publication.

CONFLICTS OF INTEREST

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. J.M. Montero-Cabezas received a research grant from Shockwave Medical and speaker fees from Abiomed, Boston Scientific, and Penumbra Inc. A. Pérez de Prado reports receiving institutional research grants from Abbott and Shockwave Medical and speaker honoraria and consulting fees from iVascular, Boston Scientific, Terumo, B. Braun, and Abbott Vascular. I.J. Amat-Santos is proctor for Boston Scientific. A. Pérez de Prado, F. Alfonso 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. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

SUPPLEMENTARY DATA

REFERENCES

INTRODUCTION

Aortic stenosis (AS) is the most common primary valvular heart disease requiring intervention.1 Its prevalence is estimated at 3–5% in individuals older than 75 years,2,3 and it is expected to increase due to longer life expectancy, growing awareness, and improved diagnostic accuracy.4 The mortality rate of untreated severe symptomatic AS reaches 10-20% within the first year and 45% at 4 years.2,5

Transcatheter aortic valve implantation (TAVI) is a well-established, less invasive alternative to surgical aortic valve replacement for patients with severe symptomatic AS.1,6 Initially reserved for high-risk patients, TAVI indications have expanded to intermediate-risk and older lower-risk patients.1,6 Improvements in device technology, procedural techniques, and operator expertise have led to fewer complications and enhanced overall safety.3 The increasing prevalence of AS and the expansion of TAVI indications highlight the need to increase procedural capacity to meet current and future clinical demands and ensure timely access to treatment.7

Current clinical practice guidelines recommend that TAVI must be performed exclusively at centers with on-site cardiac surgery (CS) backup,1,6 as surgical backup provides a safety net in complications requiring emergency cardiac surgery (ECS).8 Nonetheless, the rate of ECS has significantly decreased to 0.5-1% of TAVI,9 and the outcomes of ECS remain poor,9 with a 54% survival rate at the index event and only 22% at 1 year,10 raising concerns about the actual benefits of mandatory surgical backup.

TAVI availability remains variable, with regional disparities due to the centralized distribution of CS centers.4,11 As a result, access is often limited in regions without tertiary CS centers, leading to prolonged waiting periods associated with a worse prognosis.3 TAVI waiting list mortality rate reaches 18%, highlighting the need for timely intervention.12 Expanding TAVI to centers without on-site CS will improve access, increase procedures, reduce health care inequalities, and alleviate surgical centers, allowing them to focus on higher-risk procedures.3,13 The limited number of eligible centers constrains the national procedural volume, preventing the health system’s ability to meet the population’s growing TAVI needs.4,14

This study aims to describe our experience with TAVI in a center without on-site CS and compare outcomes to the national benchmark of centers with surgical backup.

METHODS

Study population

We conducted a retrospective, single-center cohort study including the first 300 consecutive patients who underwent TAVI at our center, Hospital Espírito Santo de Évora (Portugal), between 2020 and 2024. This study was conducted in a hospital without an on-site CS department. Patients were identified through the institutional structural heart procedure registry. The study was approved by the center ethics committee, informed consent was obtained from all participants, and the study was conducted in full compliance with the Declaration of Helsinki.

Data collection

Clinical, echocardiographic, laboratory, and procedural data were obtained from electronic health records, including imaging modalities, procedural documentation, and discharge summaries. Baseline characteristics included demographic, clinical, and echocardiographic parameters, and procedural information such as access route and valve type.

Endpoints

The primary endpoint was the 30-day all-cause mortality rate. The secondary endpoints were need for ECS, in-hospital mortality, stroke, 1-year all-cause mortality rate, 1-year cardiac death, vascular complications, major hemorrhage, and permanent pacemaker implantation. Outcomes were defined according to the Valve Academic Research Consortium-3 (VARC-3) criteria.15 ECS was defined as any unplanned cardiac surgical conversion to open surgery required to manage a life-threatening complication occurring during or shortly after the procedure, performed before the patient leaves the procedural environment.

In addition, outcomes were compared with the most recent Portuguese national TAVI registry,16 which exclusively includes centers with on-site CS, to provide a benchmark for procedural safety and efficacy profile.

Follow-up

Follow-up was performed through clinic visits at 3 and 12 months, complemented by telephone contact and review of electronic health records when in-person visits were not possible. Symptomatic improvement was evaluated based on changes in New York Heart Association (NYHA) functional class.

Statistical analysis

Categorical variables were expressed as frequencies and percentages and compared using the chi-square test or Fisher’s exact test, as appropriate. Continuous variables were assessed for normality using the Shapiro–Wilk test. Normally distributed data were expressed as mean ± standard deviation (SD) and compared using the Student t test. Non-normally distributed variables were expressed as the median and interquartile range (IQR) and compared using the Mann–Whitney U test. Statistical significance was set at a 2-tailed P-value < .05. All statistical analyses were performed using Stata version 18.0 (StataCorp, United States).

RESULTS

Baseline characteristics

The first consecutive 300 patients undergoing TAVI between 2020 and 2024 were included. The cohort mean age was 82 ± 5 years (62–101), and 54% (n = 161) were women. The median Society of Thoracic Surgery (STS) risk score was 3.8 [IQR, 2.3–6.6], with 17% (n = 51) classified as high-risk (STS > 8). Prior hospitalization for symptomatic AS occurred in 21% (n = 64). Seven patients (2%) had undergone previous surgical aortic valve replacement and were treated with the valve-in-valve procedure. Low-flow low-gradient severe AS was observed in 10% (n = 31) and bicuspid aortic valve in 6% (n = 18). The baseline characteristics of the included patients are summarized in table 1 and table 2. The Portuguese National TAVI registry included 2346 patients. Compared with our cohort, the national registry included more patients with NYHA FC > II (68% vs 51%; P < .01) and COPD (22% vs 12%; P < .01), whereas our center had a higher prevalence of chronic kidney disease (50% vs 38%; P < .01). The baseline characteristics of the Portuguese National TAVI Registry and a comparison with our cohort are shown in table 3.

Table 1. Baseline characteristics and comorbidities

Table 2. Baseline characteristics comparison between our cohort and the Portuguese TAVI registry

Table 3. Clinical context and procedural characteristics

Procedural characteristics

Most of our procedures were elective (83%; n = 249), while 17% (n = 51) were performed urgently following unplanned hospital admission for symptomatic severe AS. Cardiogenic shock was found in 5% (n = 15), and 4% (n = 12) required ventilatory support (table 3). Transfemoral access was used in 99% of cases (n = 298); the remaining 2 were performed via transcarotid and through an aortofemoral bypass graft route, both with surgical exposure by the vascular surgery team. Self-expandable valves were used in 95% of cases (n = 286), predominantly the Evolut family (Medtronic, United States) in 91%, n = 259, followed by Navitor (Abbott, United States) in 7% (n = 20) and Acurate (Boston Scientific, United States) in 2% (n = 6). The balloon-expandable valve Myval (Meril, India) was used in 5% (n = 14) (table 4).

Table 4. Procedural and follow-up outcomes

Procedural and 1-month outcomes

The primary endpoint, 30-day mortality rate, was 3.7% (n = 11), while in-hospital mortality was 2% (n = 6). Survival at the end of the procedure was achieved in 99% of patients (n = 298). No patient required ECS. Two patients (0.7%) underwent transcathether pericardiocentesis for cardiac tamponade, one due to a self-contained left ventricular guidewire perforation that did not require ECS, and the other of undetermined cause, which persisted and ultimately required delayed exploratory cardiac surgery, resulting in postoperative death. No cases of aortic valvular annulus rupture, coronary obstruction, TAVI-in-TAVI deployment, or valve embolization occurred. Stroke occurred in 2.7% (n = 8), 1.6% of which (n = 5) were disabling, while major bleeding and vascular complications were each observed in 8%. Pacemaker implantation was required in 20% (n = 61) (table 4). A detailed description of procedural and early causes of death is shown in table S1.

Follow-up outcomes

The 1-year all-cause mortality rate was 12% (n = 36), and cardiac death, 4% (n = 12). A detailed description of the causes of death is provided in table S1. Readmission occurred in 17% (n = 51), including 32 cardiovascular and 19 non-cardiovascular events. A detailed description of the causes of readmission is provided in table S1. Among surviving patients with available data, 91% reported symptomatic improvement, assessed by the NYHA functional class (table 4).

National TAVI registry comparison

Compared with the Portuguese TAVI national registry results available16 (table 5), our center demonstrated a non-statistically significant lower 30-day mortality rate (3.7% vs 4.8%; OR, 0.8; 95%CI, 0.44–1.47; P = .5) and similar 1-year mortality rates (12% vs 11%; OR, 1.0; 95%CI, 0.76–1.47; P = .8) (figure 1). The rate of ECS was equivalent in both groups (0% vs 0.4%; P = .5), as were the rates of vascular complications (8% vs 6.8%; P = .4) and major bleeding (8.3% vs 13.3%; P = .2). Our stroke rate was numerically lower (2.7% vs 4.6%; P = .1), as was the rate of acute kidney injury (6% vs 4.2%; P = .5). Pacemaker implantation rates were similar (20% vs 19%; P = .7) (figure 2). However, 1-year hospitalization was more frequent in our cohort (17% vs 9.6%; P = .03).

Table 5. Outcomes comparison between our center and the national registry

Figure 1. Forest plot comparing the odds ratios (OR) of primary endpoints between our center without on-site cardiac surgery (CS) backup and the national Portuguese TAVI registry16 (all centers with on-site CS backup).

Figure 2. Forest plot of procedural outcomes comparing our center without on-site CS backup with the national Portuguese TAVI registry16 (centers with on-site CS backup).

DISCUSSION

This single-center study is the first national experience of TAVI in a non-on-site CS backup center. Our results suggest that this model is feasible and safe, with outcomes comparable to those reported by national and international series, including centers with surgical backup. Our outcomes were similar across key endpoints vs the National Portuguese TAVI registry,16 which includes only centers with surgical backup. Although no patients from our series required ECS, and 1 patient underwent delayed surgical intervention due to persistent pericardial effusion, the procedure was unsuccessful. This observation is consistent with other reports indicating that outcomes of emergency conversion after TAVI are generally poor, even in centers with surgical backup.8,10

TAVI safety and efficacy profile have improved significantly through careful procedural planning, the involvement of a multidisciplinary heart team (including cardiac surgery), and growing operator experience supported by technological advances. As a result, the need for immediate surgical backup has become increasingly less relevant. Although the complications that require surgical intervention remain rare, they are associated with high morbidity and mortality despite surgical management. Within this context, our results support the feasibility and suggest the non-inferiority of performing TAVI without on-site CS, reinforcing its applicability across various clinical scenarios, including younger individuals and those with multivalvular or coronary artery disease.

Our program reflects the contemporary TAVI landscape, including a heterogeneous and high-risk population with a significant proportion of emergency and unstable cases, including hospitalized patients and those in cardiogenic shock. In addition, we treated patients with complex anatomical and clinical characteristics such as valve-in-valve procedures, bicuspid aortic valves, reduced LVEF, and pulmonary hypertension. This all-comers profile mirrors the real-world spectrum that structured TAVI programs must address today, extending beyond elective transfemoral procedures for native AS.

Of note, our median waiting time for the procedure was short (59 days [IQR, 22-122]), and 20% of patients were referred from outside our direct hospital catchment area. This suggests that our center has become a regional reference for TAVI despite the lack of on-site CS, which reflects both the accessibility of our program and the trust placed in our heart team’s expertise. Importantly, many of these patients were referred because traditional TAVI centers could not meet procedural demand promptly, highlighting our role in addressing unmet clinical needs within the region.

Our findings align closely with results from countries where TAVI is performed without on-site CS, including Spain,11 Germany,17 and Austria.18 In Spain, the multicenter registry reported a conversion rate to open-heart surgery of 0.3% in centers without on-site CS backup.11 The German AQUA registry, which included more than 17 000 patients, found no significant differences in outcomes between centers with and without CS, with a 30-day mortality rate of 3.8% in hospitals with visiting CS vs 4.2% in those with CS backup, with emergency surgery rates of 0.3% and 0.7%, respectively17. Similarly, a study from Austria has shown favorable outcomes in centers without on-site surgery, with no significant differences in in-hospital mortality or surgical conversion rates.18 Our outcomes are consistent with these findings, with a 30-day mortality rate of 3.7% and no cases of ECS. Consistent with previous experiences from other countries, our results demonstrate equivalent and non-inferior results compared with centers that have on-site surgical backup.

Importantly, our study reflects a more recent era, with procedures performed in lower-risk patients, using the latest-generation devices, by more experienced operators, and following more precise preoperative planning with advanced CT imaging modalities. In addition, unlike earlier studies where visiting surgeons were present, our center performed all procedures without on-site surgical support, demonstrating the feasibility of a fully independent model. This study provides contemporary real-world evidence that TAVI can be safely and effectively performed in selected patients in centers without on-site CS backup, supporting broader access while maintaining quality standards.

Our study carries important policy implications. In the context of rising TAVI demand and resource constraints in high-volume surgical centers, decentralizing care to centers without on-site CS backup may enhance access without compromising patient outcomes. Our data supports the expansion of TAVI programs under carefully controlled conditions: standardized protocols, well-trained interventional teams, strong referral networks, and access to surgical support within a structured regional pathway. Regulatory agencies may consider revisiting existing requirements for on-site surgery, fostering a model where expertise guides the safe implementation of structural heart procedures while ensuring timely access to defined surgical centers for protocoled backup in case of delayed surgical needs.

These findings highlight the safety and viability of expanding TAVI programs to selected centers without surgical backup. With rigorous patient selection, experienced operators, and standardized procedural pathways, excellent outcomes can be achieved without immediate surgical support. Our experience supports a more inclusive structural heart care model that delivers timely and effective therapy to a broader patient population without compromising safety or efficacy.

Limitations

While these results are encouraging, several limitations must be acknowledged. First, this was a single-center, retrospective study, and although data collection was comprehensive, the potential for unmeasured confounding remains. Second, long-term follow-up beyond 1 year was unavailable, limiting conclusions on valve durability and late complications. Third, patient selection and procedural planning were guided by a highly experienced heart team, which may not be generalizable to all centers without surgical backup. Finally, although the baseline characteristics of our cohort and those of the Portuguese national registry (table 3) appear to be broadly comparable, result comparisons should be interpreted with caution, as no statistical adjustment was performed, the analysis was retrospective, and patients in the registry generally had a less favorable clinical profile.

CONCLUSIONS

Our study demonstrates that TAVI can be safely and effectively performed in centers without on-site CS backup, even in a heterogeneous, all-comers population. Outcomes appear broadly comparable and support the non-inferiority of this approach relative to centers with on-site CS. The risk of ECS was very low, and its incremental benefit may be limited, while CS centers remain few and frequently overburdened. These findings suggest that, with careful case planning and growing operator experience, expanding TAVI programs to selected non-CS centers is a safe and feasible strategy to address the growing demand and improve access for patients with severe AS. Randomized controlled trials are needed to confirm these results and guide broader implementation.

DATA AVAILABILITY

The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.

FUNDING

None declared.

ETHICAL CONSIDERATIONS

This study was approved by Hospital Espírito Santo de Évora ethics committee, ULSAC. All procedures were performed in full compliance with the ethical standards of the center research committee and with the Declaration of Helsinki. Informed consent was obtained from all individual participants included in the study. This study was conducted in full compliance with the SAGER guidelines. Sex and gender considerations were addressed appropriately, and any potential sex- or gender-related differences were assessed and reported where relevant.

STATEMENT ON THE USE OF ARTIFICIAL INTELLIGENCE

No artificial intelligence tools were used in the preparation of this manuscript.

AUTHORS’ CONTRIBUTIONS

A. Rocha de Almeida: conceptualization, methodology, data curation, formal analysis, investigation, original draft writing and review and editing of the final draft. R. Fernandes, Â. Bento, D. Neves, D. Brás, G. Mendes were in charge of original draft writing and review and editing of the final draft. R. Rocha, M. Paralta Figueiredo and R. Viana were in charge of data curation, reviewed and edited the final draft. R. Louro and Á. Laranjeira Santos were in charge of review and editing of the final draft. L. Patrício was in charge of conceptualization, supervision, review and editing of the final draft and validation. All authors read and approved the final draft.

CONFLICTS OF INTEREST

None declared.

SUPPLEMENTARY DATA

REFERENCES