Intravascular lithotripsy (IVL) has emerged as a viable treatment option for calcified coronary lesions. This study aimed to identify clinical and procedural factors associated with major adverse cardiovascular events (MACE) following IVL. This retrospective analysis included 583 patients (72.9 ± 9 years, 74% male) treated with IVL for 612 lesions from the multicenter BENELUX-IVL registry (May 2019-December 2024). Kaplan–Meier analysis was performed to evaluate survival probability. Binary logistic regression analysis was performed to identify predictors of MACE, including cardiac death, nonfatal myocardial infarction (MI) or clinically driven target vessel revascularization (TVR) at 1-year follow-up. Patients presented with acute coronary syndrome in 246 cases (42%), while a variety of target lesions was treated, including in-stent lesions ( n = 185, 30%), aorta-ostial lesions ( n = 148=24%), bifurcation lesions ( n = 135, 22%) and chronic total occlusions (CTOs)( n = 45, 7%). MACE occurred in 44 patients (11%) at 1-year and in 53 patients (18%) at 2-years follow-up. Occurrence of procedural complications (p <0.001), CTOs (p = 0.020), in-stent lesions (p = 0.044), post-IVL plaque modification (p = 0.003) and greater postprocedural residual diameter stenosis on fluoroscopy (p = 0.006) were associated with the occurrence of MACE, while MI in the medical history (p = 0.001) was negatively associated with MACE. Following treatment with IVL in a real-world registry, clinical outcomes up to 2-years follow-up were favorable. Procedural complications, CTOs, in-stent lesions, performance of post-IVL plaque modification and greater postprocedural residual diameter stenosis on fluoroscopy were independent risk factors for experiencing MACE at 1-year follow-up. In contrast, a history of MI was associated with a lower risk of MACE.
Coronary artery calcification (CAC) is an established factor increasing the complexity of percutaneous coronary interventions (PCIs), as it limits optimal stent expansion and is associated with worse acute procedural success rates, leading to higher levels of adverse clinical outcomes. ,, The prevalence of CAC during PCI is growing due to the higher age of patients treated and the growing burden of comorbidities such as diabetes and chronic kidney disease. ,, Therefore, evaluating therapeutic strategies to optimize lesion preparation in CAC is crucial to enhance patient outcomes. ,
Intravascular lithotripsy (IVL) has emerged as treatment strategy for CAC. The working mechanism of IVL is based on the emission of acoustic shockwaves from the IVL-balloon that selectively induce (micro) fractures in coronary calcium, thereby improving vessel compliance and enabling better deployment and expansion of stents. ,
IVL has demonstrated favorable safety and efficacy profiles in the treatment of CAC, with high procedural success rates, low complication rates and good midto-longer term clinical outcomes with most of the evidence coming from observational studies. , However, the clinical and procedural factors influencing major adverse cardiovascular events (MACE) after IVL in an real-world patient cohort remains unclear as previous studies evaluated predictors of MACE in highly selected patient populations. , This limits the ability to further enhance patient outcomes after IVL.
This study aimed to fill this gap by identifying clinical and procedural factors associated with MACE following IVL within a real-world all-comers patient cohort from the BENELUX-IVL Registry.
Methods
Population and data collection
Data for performance of this study were derived from the all-comers international multicenter BENELUX-IVL registry (NCT06577038), in which patients (≥18 years) who underwent PCI for CAC with IVL were enrolled across 9 centers in 3 European countries between May 2019 and December 2024. IVL was performed in all cases with the Shockwave IVL Coronary System (Shockwave Medical, Santa Clara, California). Technical decisions regarding the IVL-procedure (timing, balloon size, number of pulses delivered and the inflation pressure) and further treatment strategy (performance of pre and postdilatation, stent placement, and use of intracoronary imaging (ICI)) were left to the operator’s discretion. All data were collected form the hospital’s electronic health records, and included demographic, clinical, procedural and follow-up data. Imaging data, including angiographic and ICI, were analyzed in a centralized corelaboratory at the Leiden University Medical Center. 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 center.
Definitions and imaging analysis
The complexity of the coronary artery disease was graded according to the SYNTAX score algorithm when all 3 vessels were recorded. 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 noncompliant balloon underexpansion) and by ICI when available. Angiographically, 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). 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. ,, On ICI, a calcium arc ≥270 degrees was considered as severe calcification.
Quantitative coronary analysis (QCA) and ICI were retrospectively analyzed offline to evaluate treatment success following IVL and subsequent therapy. QCA was used exclusively to assess coronary angiograms, and was performed pre-IVL and post-IVL and stenting, using Medis Suite QCA (2D/3D) software (Medis Suite 4.0.24.4; Medis Medical Imaging System BV, Leiden, The Netherlands). Measurements included the minimum lumen diameter (MLD) and percentage diameter stenosis (percentage DS). Analysis of IVUS and OCT was performed using QCU-CMS 4.69 (Leiden University Medical Center, Leiden, The Netherlands).
Study endpoints
The primary endpoint of this study was the occurrence of MACE at 1-year and 2-year follow-up, defined as the composite of cardiac death, nonfatal target vessel myocardial infarction (MI) or clinically driven target vessel revascularization (TVR). The secondary endpoint was the postprocedural residual diameter stenosis percentage on fluoroscopy, as assessed by QCA. Additionally, 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 Thrombolysis In Myocardial Infarction (TIMI) 3 flow and a residual stenosis <30% assessed by QCA and/or fluoroscopically by the treating physician) and procedural success (technical success without in-hospital MACE) were assessed. Complications were assessed by the treating physician and documented in the patient records and were validated by a systematic retrospective analysis of the coronary angiograms by the centralized corelaboratory.
Statistical analysis
Continuous variables are presented as either the mean ± standard deviation or median with interquartile range (25 th-75 th percentile), as appropriate. Categorical variables were reported as frequencies and percentages. Kaplan–Meier analysis was performed to estimate cumulative survival free of MACE at 1-year follow-up. Based on clinical relevance, the relationships between selected clinical and procedural variables and occurrence of MACE at 1-year follow-up, were analyzed using univariable binary logistic regression. Variables with a p-value <0.3 on univariate analysis were entered in multivariable models to account for potential confounding factors and identify factors independently associated with MACE. Results from the binary logistic regression are reported as odds ratios (OR) with 95% confidence intervals (CIs) and p-values. Statistically significance was defined as a 2-sided p-value <0.05. All statistical analyses were performed with SPSS for Windows version 25.0 (IBM, Armonk, New York) and R version 4.4.0 (R Foundation for Statistical Computing, Vienna, Austria) with RStudio version 2024.04.2 Build 764 (Posit, PBC, Boston, MA).
Results
Baseline characteristics
583 patients were treated with IVL with a mean age of 72.9 ± 9.0 years and 74% were male. The study population was characterized by a high prevalence of comorbidities, including hypertension (71%) and hypercholesterolemia (54%). 246 (42%) patients presented with an acute coronary syndrome (ACS). A detailed overview of the baseline demographics and medical history is provided in Table 1 .
Table 1
Baseline demographics and medical history
| Overall ( n = 583) | |
|---|---|
| Age, years | 72.9 ± 9.0 |
| Male, n (%) | 431 (74) |
| Diabetes, n (%) | 193 (33) |
| Hypertension, n (%) | 414 (71) |
| Hypercholesterolemia, n (%) | 316 (54) |
| Family history of CAD, n (%) | 144 (25) |
| Chronic kidney disease (GFR<60ml/min/1.73m 2), n (%) | 176 (30) |
| Syntax score | 21.4 ± 12.6 |
| Fluoroscopic calcification ( n = 440) | |
| Not possible, n (%) | 48 (11) |
| None/mild, n (%) | 35 (8) |
| Moderate, n (%) | 82 (19) |
| Severe, n (%) | 275 (63) |
| Left ventricular ejection fraction( n = 466) | |
| Good (>50%) | 307 (66) |
| Reasonable (30%-50%) | 113 (24) |
| Poor (20%-30%) | 24 (5) |
| Very poor (<20%) | 4 (1) |
| Unknown | 18 (3) |
| Smoking history, n (%) | 242 (42) |
| Previous stroke, n (%) | 75 (13) |
| Previous MI, n (%) | 212 (36) |
| Previous PCI, n (%) | 265 (46) |
| Previous CABG, n (%) | 105 (18) |
| Clinical presentation | |
| Chronic coronary syndrome, n (%) | 337 (58) |
| Acute coronary syndrome, n (%) | 246 (42) |
| Stable angina, n (%) | 282 (48) |
| Unstable angina, n (%) | 63 (11) |
| NSTEMI, n (%) | 149 (26) |
| STEMI, n (%) | 34 (6) |
| Other, n (%) | 55 (9) |
CABG = coronary artery bypass graft surgery; CAD = coronary artery disease; MI = myocardial infarction; NSTEMI = non-ST-segment elevation myocardial infarction; PCI=percutaneous coronary intervention; STEMI=ST-segment elevation myocardial infarction.
Procedural characteristics
The procedural and lesion characteristics are summarized in Table 2 . 612 IVL procedures were performed, with a median balloon diameter of 3.5 (3.0-4.0) and 80 (60-80) pulses delivered. The left anterior descending artery (LAD) was the most frequent target vessel ( n = 277, 45%), followed by the right coronary artery (RCA; n = 212, 35%) and left circumflex artery (LCx; n = 98, 16%). The left main (LM) was involved in 67 cases (11%). A variety of target lesions was treated, including in-stent lesions ( n = 185, 30%), aorta-ostial ( n = 148=24%), bifurcations ( n = 135, 22%) and chronic total occlusions (CTOs) ( n = 45, 7%). pre and postdilatation were performed both in 91% of the procedures, while other plaque modification techniques next to IVL were used in 91 (15%) lesions. These plaque modification techniques were predominantly performed before IVL ( n = 82, 15%), most commonly using rotational atherectomy (RA; n = 75, 12%). Post-IVL plaque modification was less frequent ( n = 10, 2%) and similarly consisted mostly of RA ( n = 5, 1%), followed by ultrahigh pressure (OPN) balloon inflation ( n = 3, 0.5%) and cutting and scoring balloons (each n = 1, 0.2%). For therapy completion, stents were implanted in 476 (78%) target lesions, while drug coated balloons were inflated in 46 (8%). During therapy, ICI was used for treatment guidance and treatment optimization in 294 lesions (48%), and was performed mostly after therapy completion ( n = 243, 40%).
Table 2
Procedural and lesion characteristics
| Overall ( n = 612) | |
|---|---|
| Target vessel | |
| LM, n (%) | 67 (11) |
| LAD, n (%) | 277 (45) |
| LCx, n (%) | 98 (16) |
| RCA, n (%) | 212 (35) |
| SVG, n (%) | 6 (1) |
| Arterial graft, n (%) | 1 (0.2) |
| Lesion characteristics | |
| Bifurcation, n (%) | 135 (22) |
| Ostial, n (%) | 148 (24) |
| Tortuous, n (%) | 15 (3) |
| CTO, n (%) | 45 (7) |
| Long-segment, n (%) | 399 (65) |
| In-stent, n (%) | 185 (30) |
| IVL | |
| Balloon diameter, mm | 3.5 (3.0-4.0) |
| Number of pulses | 80 (60-80) |
| Predilatation, n (%) ( n = 552) | 500 (91) |
| Predilatation balloon diameter, mm | 3.0 (2.5-3.5) |
| Predilatation balloon maximum pressure (atm) | 19.3 ± 4.4 |
| Postdilatation, n (%) ( n = 552) | 504 (91) |
| Postdilatation balloon diameter, mm | 3.5 (3.5-4.0) |
| Postdilatation balloon maximum pressure (atm) | 19.5 ± 4.5 |
| IVL after stenting (bail-out), n (%) | 82 (13) |
| ICI performed, n (%) | 294 (48) |
| Pre-IVL, n (%) | 224 (37) |
| Post-IVL, n (%) | 243 (40) |
| Other plaque modification technique used, n (%) | 91 (15) |
| Pre-IVL | 82 (13) |
| RA, n (%) | 75 (12) |
| Cutting balloon, n (%) | 5 (1) |
| Scoring balloon, n (%) | 1 (0.2) |
| OPN balloon, n (%) | 1 (0.2) |
| Post-IVL | 10 (2) |
| RA, n (%) | 5 (1) |
| Cutting balloon, n (%) | 1 (0.2) |
| Scoring balloon, n (%) | 1 (0.2) |
| OPN balloon, n (%) | 3 (0.5) |
| Treatment after IVL | |
| Stent implantation, n (%) | 476 (78) |
| Stent diameter, mm | 3.5 (3.5-4.0) |
| Stent length, mm | 38 (24-59) |
| Drug-coated balloon, n (%) | 46 (8) |
| Procedural time, min | 81 (59-110) |
| Fluoroscopy time, min | 23 (16-36) |
| Contrast volume, ml | 170 (130-230) |
CTO = chronic total occlusion; ICI = intracoronary imaging; IVL = intravascular lithotripsy; IVUS = intravascular ultrasound; LAD = left anterior descending artery; LCx = left circumflex artery; LM = left main; OCT = optical coherence tomography; OPN = ultra-high pressure balloon; RA = rotational atherectomy; RCA = right coronary artery; SVG = saphenous venous graft.
Procedural outcomes
Procedural success was achieved in 518 (89%) of the target lesions ( Table 3 ). Device and technical success were achieved in 97% and 90%, respectively. In total, 35 (6%) procedural complications occurred, of which 7 (1%) occurred immediately after IVL. The most frequently occurring complications were coronary dissections ( n = 9, 2%), hemodynamic instability requiring intervention ( n = 8, 2%) and coronary perforations ( n = 8, 1%).
Table 3
Procedural outcomes and complications
| Overall ( n = 454) | |
|---|---|
| Procedural outcomes | |
| Device success, n (%) | 566 (97) |
| Technical success <30%, n (%) | 524 (90) |
| Procedural success <30%, n (%) | 518 (89) |
| Complications, n (%) | 35 (6) |
| Coronary dissection, n (%) | 9 (2) |
| Coronary perforation, n (%) | 8 (1) |
| Slow flow, n (%) | 1 (0.2) |
| No reflow, n (%) | 2 (0.3) |
| Abrupt vessel closure, n (%) | 5 (1) |
| Hemodynamic instability, requiring intervention, n (%) | 9 (2) |
| Reanimation status, n (%) | 5 (1) |
| Other, n (%) | 5 (1) |
| Directly related to IVL, n (%) | 7 (1) |
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