WHAT IS ALREADY KNOWN ON THIS TOPICWHAT THIS STUDY ADDS

This real-word registry of 454 patients demonstrates IVL’s safety and efficacy across diverse clinical and anatomical scenarios, including those previously excluded from IVL studies.

The use of IVL has evolved since its introduction, with increased adoption in acute coronary syndromes and in combination with intracoronary imaging.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

These findings support the expanded use of IVL in complex coronary interventions and suggest the need for larger prospective studies to validate its efficacy in various indications, particularly in acute settings.

Introduction

Coronary artery calcification (CAC) is increasingly encountered in patients undergoing percutaneous coronary intervention (PCI), currently encompassing about up to one-fourth of the cases.1 2 CAC is associated with worse acute procedural success rates, increased in-hospital major adverse cardiovascular event (MACE) rates and worse long-term outcomes (in-stent restenosis, stent thrombosis, target vessel revascularisation and death).1 3–6 Different plaque modification techniques have been developed to treat CAC and improve stent expansion and patient outcomes.7–9 Intravascular lithotripsy (IVL) is a relatively new technique designed to modify CAC. This balloon-based method generates shock waves at low pressure from emitters inside the balloon. These shock waves specifically target calcium deposits superficially and deeply embedded in the vessel wall. The energy from the shock waves fractures the calcium, facilitating use and expansion of balloons and stents in the affected calcified lesions.10–13 IVL has been established as a safe and effective treatment option for (severe) CAC, evaluating predominantly stable patients in prespecified clinical scenarios, typically excluding patients admitted with features as, for instance, acute coronary syndrome (ACS).12 Rapid expansion of the technique has led to application in different clinical and anatomical scenarios (eg, bifurcations, in-stent stenosis, chronic total occlusions (CTOs)) and in combination with plaque modification techniques. However, scientific evidence for these broader applications of IVL is limited. In addition, the longer term outcomes after IVL therapy are yet to be studied.

Therefore, the aim of this study was to evaluate contemporary utilisation patterns, safety and efficacy of IVL in an unselected real-world patient cohort both acutely and at 1-year follow-up.

MethodsPopulation and data collection

In this all-comers international multicentre registry, patients (>18 years) who underwent PCI for CAC with IVL were retrospectively enrolled across seven centres in two European countries between May 2019 and February 2024. IVL was performed in all cases by using the Shockwave Intravascular Lithotripsy Coronary System (Shockwave Medical, Santa Clara, California). Decisions regarding technical aspects of IVL (timing, balloon size, number of pulses delivered, maximal inflation pressure), utilisation of high-pressure predilatation and postdilatation, supplementary stent placement and use of intracoronary imaging (ICI) for procedural optimisation were left to the operator’s discretion, with subsequent documentation of these decisions. Demographic, clinical, procedural and follow-up data were collected from the hospital electronic records. Angiographic and ICI data were analysed in a centralised core laboratory at the Leiden University Medical Center. Additional analyses were conducted in order to evaluate temporal trends in the use of IVL. In order to do this, patients were categorised based on the first half and the second half of the inclusion period (determined by the time span between the first and last enrolment). Patients who were unable to provide informed consent were excluded from the study.

Definitions and imaging analysis

Diagnostic angiograms were graded in the centralised core laboratory according to the SYNTAX Score algorithm if all three vessels were recorded.14 The presence of CAC was determined by the operator during the procedure both angiographically (fluoroscopic visibility of radiopacities in the vessel wall at the site of stenosis and/or non-compliant balloon underexpansion) and by ICI when available. Angiographic CAC was scored none/mild, moderate (when the radiopacities were only visible during the cardiac cycle before contrast injection) or severe (when the radiopacities were apparent without cardiac motion before contrast injection).8 15 On intravascular ultrasound (IVUS), CAC was defined as a hyperechoic signal with acoustic shadowing, while on optical coherence tomography (OCT), CAC appeared as a signal-poor area with sharply delineated borders.5 6 8 16

Quantitative coronary analysis (QCA) and ICI were retrospectively analysed offline to evaluate luminal gain following IVL. QCA was performed pre-IVL and post-IVL and stenting using Medis Suite QCA (2D/3D) software (Medis Suite V.4.0.24.4; Medis Medical Imaging System, Leiden, The Netherlands). Measurements included minimum lumen diameter (LD), minimum lumen area (LA), percentage diameter stenosis (DS) and percentage area stenosis (AS). Analysis of IVUS and OCT was performed using QCU-CMS V.4.69 (Leiden University Medical Center, Leiden, The Netherlands). When available, ICI measurements were performed, including reference vessel diameter (RVD), reference vessel area (RVA), minimum LD, minimum LA and minimum stent area (MSA). Percentage DS and percentage AS were calculated using the formulas ([RVD-Minimum LD]/RVD)*100 and ([RVA-Minimum LA]/RVA)*100, respectively. Stent expansion was determined with the formula (MSA/RVA)*100, and the eccentricity index was computed by subtracting the minimum LD from the maximum LD at the minimum LA and dividing it by the latter. Lastly, we documented the maximum calcification angle and thickness pre-IVL. The specified variables were compared between the first available recording pre-IVL and after IVL and stenting.

Study endpoints

The primary endpoint of the study was procedural success, defined as a composite of residual stenosis <30% (assessed by QCA and/or fluoroscopically by the treating physician), final thrombolysis in myocardial infarction (TIMI) 3 coronary flow and absence of in-hospital MACE (cardiac death, non-fatal target vessel myocardial infarction (MI) or clinically driven target vessel revascularisation). Secondary endpoints included device success (defined as successful employment of the IVL catheter to the target lesion and delivery of IVL pulses without direct angiographic complications), technical success (defined as the presence of TIMI 3 flow and a residual stenosis <30% assessed by QCA and/or fluoroscopically by the treating physician) and the occurrence of MACE and all-cause mortality before discharge and at 1-year follow-up after IVL.

Complications were assessed by the treating physician and documented in the patient records. They were considered IVL related if they occurred immediately following the IVL treatment. This was further confirmed through a systematic retrospective analysis of the coronary angiograms by the centralised core laboratory.

Statistical analysis

Continuous variables are presented as either the mean±SD or median with IQR (25th–75th percentiles), as appropriate. Differences between paired continuous variables were assessed with the paired t-test if normally distributed, otherwise the Wilcoxon signed-rank test was used. Differences between unpaired continuous variables were assessed with the unpaired t-test if normally distributed, and with the Mann-Whitney U test if not normally distributed. Categorical variables were reported as frequencies and percentages and analysed using the χ² test for expected counts ≥5 per cell, while Fisher’s exact test was applied for variables with expected counts <5 per cell. Kaplan-Meier analysis was performed to estimate cumulative survival free of MACE at 1-year follow-up. Statistical analysis was performed with SPSS V.25.0 for Windows (IBM). All tests were two sided, and a p value <0.05 was considered statistically significant. No adjustments for multiple comparisons were made.

Results

A total of 454 patients (aged 73.2±9.0 years and 75% male) underwent IVL for 477 calcified lesions. The baseline patient characteristics are displayed in table 1 and the procedural and lesion characteristics in table 2. 252 (56%) patients presented with chronic coronary syndrome (CCS), while 202 (44%) had ACS, according to the European Society of Cardiology guidelines.17 The left anterior descending artery (n=212, 44%) was the most frequently treated target vessel, while the left main (LM) was involved in 57 (12%) lesions. In addition, diverse lesion subtypes were involved, including bifurcation (n=111, 23%), ostial (n=96, 20%) (figure 1), in-stent (n=168, 35%) and CTO (n=33, 7%) lesions (figure 2). The average SYNTAX Score was 22.0±13.6.

Table 1

Baseline demographics and medical history

Table 2

Procedural and lesion characteristics

Figure 1

Use of intravascular lithotripsy (IVL) for an ostial calcified lesion. (A) Baseline angiogram with a severely calcified target lesion at the ostial left main (LM, arrow). (B) Angiogram after predilatation. (C) Optimal coherence tomography (OCT) after predilatation, showing 180 degrees calcification with 5 mm thickness, treated with IVL (40 pulses) (D). (E) Post-IVL and postdilatation angiogram with excellent stent expansion (arrow), confirmed by OCT, which also showed calcium fracture (asterisk) (F).

Figure 2

Use of intravascular lithotripsy (IVL) for a calcified chronic total occlusion (CTO). (A) Baseline angiogram with a CTO at the mid-left anterior descending artery (LAD, arrow). (B) Intravascular ultrasound (IVUS), showing 360 degrees calcification after predilatation, treated with 80 pulses IVL (C). (D) Post-IVL IVUS, showing calcium fracture (asterisk). (E) Angiogram after stenting and postdilatation, showing excellent stent expansion (arrow) and confirmed by IVUS (F).

The mean IVL balloon diameter was 3.5±0.5 mm and delivered a median of 80 (60–80) pulses to the target lesion. In the majority of target lesions, high-pressure predilatation and postdilatation was performed (93% and 94%, respectively). Additional plaque modification techniques were employed in 77 (16%) cases, most of them (n=69, 15%) prior to IVL, with rotational atherectomy (RA) the most frequently used (n=62, 13%). The post-IVL treatment consisted of stent implantation (n=369, 77%) and use of a drug-coated balloon (DCB) (n=34, 7%). The stents had a median diameter of 3.5 (3.5–4.0) mm and median length of 38 (24–60) mm. In addition, 81 (17%) IVL procedures were performed as bail-out therapy after stenting. In most of these cases, high-pressure postdilatation (n=74, 91%) was performed while stents were implanted in 16 (20%). In 22 (5%) cases, two IVL balloons were used. Of these, 14 (3%) cases required a larger IVL balloon proximally for effective therapy. In five (1%) cases, the initial balloon ruptured or malfunctioned, and in three (1%) cases, a second IVL balloon was used due to unsatisfactory results with the first one.

ICI was performed for procedural optimisation in 249 (52%) target lesions (table 2). 186 (39%) recordings were made pre-IVL—167 (35%) with IVUS and 22 (5%) with OCT. Post-IVL, 206 (43%) recordings were made, with 184 (39%) using IVUS and 22 (5%) using OCT. The median calcium arc was 360 (223–360) degrees, with a mean thickness of 1.0±0.3 mm on OCT. Paired ICI recordings were available for analysis in 125 target lesions. There was a significant improvement after IVL and stenting of the minimum LD (1.9 (1.7–2.3) mm vs 3.3 (2.8–3.6) mm; p<0.001), minimum LA (4.0 (2.8–4.9) mm2 vs 9.6 (7.7–11.5) mm2; p<0.001), percentage DS (50.8±12.9 vs 22.7±10.7; p<0.001), percentage AS (71.3 (60.1–78.9) vs 27.4 (19.5–37.4); p<0.001), MSA (5.3±2.0 mm2 vs 8.7±2.2 mm2; p<0.001) and stent expansion (42.7±15.4 vs 65.1±14.2; p<0.001) (table 3). On QCA analysis, available in 408 (86%) lesions, the minimum LD (1.0±0.7 mm vs 2.9±0.7 mm; p<0.001) and percentage DS (67.7±20.5 vs 16.8±10.4; p<0.001) improved significantly after IVL and stenting, with a mean diameter gain of 1.9±0.9 mm.

Table 3

Quantitative coronary and intracoronary imaging analysis

Device success was achieved in 443 (98%) patients. In the remaining patients, the IVL balloon could not cross the target lesion in six (1%) patients, and IVL-related complications occurred in another six (1%). Technical success and procedural success were achieved in 411 (91%) and 405 (89%) patients, respectively (table 4). The IVL-related complications consisted of two controlled coronary dissections (0.4%) caused by fracture of calcium, two cases of haemodynamic instability (0.4%), one coronary perforation after IVL balloon rupture (0.2%), one abrupt vessel closure (0.2%), one patient requiring resuscitation (0.2%) and one episode of periprocedural ventricular fibrillation (0.2%) and were all successfully treated. Most other complications were related to high-pressure postdilatation.

Table 4

Procedural outcomes and complications

During a median follow-up of 365 (166–365) days, with complete 1-year follow-up present in 283 (62%) patients, MACE was observed in 37 (13%) patients and included 11 (4%) cardiac deaths, 10 (4%) non-fatal target vessel MIs and 23 (8%) clinically driven target vessel revascularisations. All-cause mortality occurred in 34 (12%) patients (figure 3 and table 5). In-hospital follow-up was present for all patients, in which adverse cardiovascular events occurred in 10 (2%). These events included eight cardiac deaths: five due to cardiogenic shock or hypovolaemic shock after PCI, two sudden cardiac arrests and one caused by an iatrogenic aortic root dissection after high-pressure postdilatation. Additionally, two clinically driven target vessel revascularisations occurred: one emergency coronary artery bypass graft surgery for a coronary dissection caused by predilatation and one PCI for thrombus embolisation.

Figure 3

One-year major adverse cardiovascular event (MACE)-free survival of patients treated with intravascular lithotripsy. MI, myocardial infarction; TVR, target vessel revascularisation.

Table 5

Major adverse cardiovascular events and all-cause mortality

Additional analysis (online supplemental table 1) to evaluate trends in the use of IVL revealed more use of IVL in patients with ACS in the second inclusion period (33% in the first period vs 48% in the second period; p=0.004). Similarly, there was an increase in the use of ICI (40% in the first period vs 57% in the second period; p=0.002) and DCBs (3% in the first period vs 9% in the second period; p=0.021), whereas calcium modification techniques were used more in the first period (22% in the first period vs 14% in the second period; p=0.034).

Discussion

This study evaluated the safety and efficacy of IVL for the treatment of CAC in real-world practice, acutely and over a 1-year follow-up period. In addition, it provides insights in current standards of use of IVL in combination with other calcium modification techniques and across various clinical and anatomical scenarios. The main findings of the study are: (1) IVL showed high success rates across diverse clinical and anatomical conditions; (2) the high success rates were accompanied by low IVL-related complication and MACE rates at 1-year follow-up; and (3) the use of IVL in patients with ACS and in combination with ICI increased over time, whereas less calcium modification devices were used.

Since the introduction of IVL, a lot of studies have been performed to evaluate its safety and efficacy, of which the DISRUPT-CAD studies are the most widely known studies prospectively enrolling patients undergoing IVL for calcified lesions. The DISRUPT-CAD studies showed good procedural success rates with low associated complication rates and low short-term (30 days) MACE rates.12 However, these studies excluded patients admitted for ACS, lesion subtypes as CTOs, saphenous venous grafts, in-stent restenosis, LM disease and patients in cardiogenic shock. The present study also included patients with these high-risk features that are under-represented in the DISRUPT-CAD studies (Tables 1 and 2).18 Even in this real-world practice, good procedural success rates (89%) and low IVL-related complication rates (1%) were observed. Our results align with a recent meta-analysis that evaluated the safety and efficacy of IVL before stent implantation in a similar patient population in terms of age, sex and clinical presentation.19 While a detailed analysis of outcomes across specific lesion subtypes is beyond the scope of this study, our findings underscore IVL’s potential as a safe and effective treatment for CAC, even in complex patients. Additionally, the safety and efficacy of IVL for in-stent lesions and CTOs has been suggested in recent individual observational studies.20 21 However, future studies should focus on assessing the outcomes for different lesion subtypes in more detail.

The follow-up results have shown to be good for a longer term follow-up period with 13% incidence of MACE over 1-year follow-up. This is higher than the reported 1-year MACE rate in the Japanese DISRUPT-CAD IV study which reported an incidence of 9.4%.22 However, similar to the earlier DISRUPT-CAD studies, this study did not include patients with ACS, heart failure and a history of recent MI, stroke or transient ischaemic attack, which may have led to a lower risk of MACE at baseline. Furthermore, this 1-year MACE rate of 13% is still lower compared with studies evaluating patients treated with other calcium modification devices like, for instance, RA, with a reported overall 9-month MACE rate of 24.2% in the ROTAXUS trial.23 Thus, the results of this study suggest that the good acute results of IVL are consistent in the longer term as well.

Trends were observed in more frequent utilisation of ICI in combination with IVL (online supplemental table 1). The increasing adoption of ICI will potentially enhance patient outcomes even further in the future. Employing ICI before IVL allows for a detailed assessment of the lesion morphology, leading to a better tailored treatment approach. In addition, this trend may have led to a reduced need of additional calcium modification techniques, like RA. Moreover, different modification devices might be used when the results of another less tailored (not ICI-guided) device had non-satisfactory results. This is, for instance, the case in Rotatripsy, where IVL might be used after treatment failure of RA.24 In this way, ICI may contribute to more effective therapy with less treatment failures. Another explanation for the reduced use of other calcium modification devices may be that IVL is easier to use, has a quicker learning curve and has been linked to shorter procedural times (compared with RA).25 Additionally, RA has limitations in targeting deep calcium within the vessel wall and may struggle with eccentric lesions due to wire bias, whereas IVL is versatile and effective in treating a wider range of calcification patterns.7–9 The combination of increased upfront ICI utilisation for treatment planning and the simplicity and effectiveness of IVL in most balloon-crossable calcified lesions likely explains for the decline in the use of other calcium modification devices such as RA. However, future randomised clinical trials are needed to compare efficacy of IVL with other calcium modification devices across different lesion types to determine the most effective strategies for specific calcification patterns and further improve patient outcomes.

ICI can be used up front for lesion assessment and treatment planning and to evaluate treatment success after IVL (by assessing calcium fractures; figures 1 and 2) and following stenting (by assessing stent apposition and expansion). The increased use of ICI, therefore, allows operators to refine the treatment strategy as needed, ultimately aiming to improve patient outcomes. Due to the observational study design, it was not possible to standardise ICI recordings or to conduct a detailed comparison in outcomes between ICI-guided and angiography-guided PCI with IVL. However, the potential long-term benefits on patient outcomes of ICI-guided compared with angiography-guided PCI are under evaluation in the IVUS-CHIP trial.

Furthermore, there has been a notable increase in the application of IVL in patients with ACS. As operators are getting more accustomed to the IVL technique over time, they will probably be more likely to use it in patients with acute admissions. In the REPLICA-EPIC18 study, the short-term MACE rates for both patients with ACS and CCS were low, with a non-significant trend of MACE in patients with ACS.26 The results of our study, with almost half of the patients (44%) admitted for ACS, also indicate low MACE rates acutely and on the longer term, suggesting that IVL can also be safely used in patients with ACS. However, validation of this finding in larger prospective studies is needed.

Limitations

This study has several limitations that should be considered. First of all, it has an observational design. This is particularly relevant when interpreting the clinical outcomes observed. Additionally, the decisions regarding the timing of IVL, the utilisation of high-pressure predilatation and postdilatation, the placement of supplementary stents and the use of ICI for procedural optimisation were left to the operator’s discretion. The lack of routine use of ICI before and after IVL limited our ability to assess the stand-alone effects of IVL treatment and to detect the presence of calcified nodules.

Conclusion

In this real-world registry, IVL demonstrated efficacy and safety across diverse clinical and anatomical settings. High success rates and low complication rates were observed, with few patients experiencing MACE acutely and at 1-year follow-up. Utilisation patterns evolved over time, with increased adoption in acute scenarios and alongside ICI.

Data availability statement

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

Ethics statementsPatient consent for publication

Not applicable.

Ethics approval

The study was exempted by the Medical Research Ethics Committee Leiden Den Haag Delft (reference number: N22.199/HL/hl), and the retrospective analysis of clinically collected data was approved by the local ethical committees at each participating centre.