Diabetes mellitus (DM) is associated with increased coronary calcification and adverse outcomes after percutaneous coronary intervention (PCI), yet the performance of intravascular lithotripsy (IVL) in this high-risk population remains insufficiently defined. This study, conducted within the all-comers BENELUX-IVL registry, evaluated the safety and efficacy of IVL-assisted PCI in patients with and without DM. The primary endpoint was major adverse cardiovascular events (MACE) at 1 and 2 years, defined as cardiovascular death, nonfatal myocardial infarction, or clinically driven target vessel revascularization. Secondary endpoints included procedural outcomes, complications, and all-cause mortality. A total of 574 patients were included, of whom 193 (33.6%) had DM and 381 (66.4%) did not. Procedural (87.0% vs 89.5%; p = 0.381) and device success (95.3% vs 97.9%; p = 0.087) were similar between groups. Post-PCI minimum lumen diameter (2.80 ± 0.59 vs 2.95 ± 0.70 mm; p = 0.027) and area (6.0 [4.80 to 7.75] vs 6.6 [4.98 to 8.90] mm²; p = 0.045) were smaller in patients with DM. Thirty-day MACE was higher among diabetics (3.1% vs 0.3%; p = 0.007), whereas 1- and 2-year MACE and mortality rates were comparable. Diabetes was not independently associated with mortality (adjusted OR 1.51; p = 0.17). In conclusion, IVL-assisted PCI is safe and effective in diabetic patients, with long-term outcomes comparable to those without diabetes, although the higher early MACE risk, particularly in type 1 DM, warrants careful procedural planning and follow-up.
Diabetes mellitus (DM) affects approximately one in three patients undergoing percutaneous coronary intervention (PCI) and is a well-established predictor of adverse cardiovascular outcomes. , Diabetic patients often present with diffuse, heavily calcified coronary artery disease (CAD), which complicates lesion preparation and stent deployment, and contributes to higher rates of restenosis and stent thrombosis. ,,, In addition, microvascular dysfunction and a systemic proinflammatory and prothrombotic state further impair outcomes after PCI. , Intravascular lithotripsy (IVL) is an emerging calcium modification technology that uses acoustic pressure waves to fracture intimal and medial calcium, thereby improving vessel compliance and facilitating optimal stent expansion. While IVL has demonstrated favorable procedural and clinical outcomes in general populations with calcified lesions, its performance in patients with DM remains insufficiently characterized. Given the unique anatomical and pathophysiological features of CAD in diabetic patients, such as medial calcification, longer lesion length, and more frequent multivessel disease, there is a clear need to specifically evaluate the efficacy and safety of IVL in this higher-risk population. ,,, In this multicenter study using data from the BENELUX-IVL registry, we aimed to assess procedural success, complication rates, and long-term clinical outcomes of IVL-assisted PCI in patients with versus without DM. This analysis further explored whether DM influences the safety and durability of IVL-assisted PCI in real-world practice.
Methods
Study population and data collection
This multicenter retrospective study included consecutive adult patients (≥18 years) who underwent PCI with IVL between May 2019 and September 2024. Patient data were obtained from the BENELUX-IVL registry (NCT06577038), a prospective, international all-comers database of patients treated with IVL for coronary artery calcification (CAC). Patients were stratified based on the presence or absence of DM. Patients with missing data on diabetic status were excluded, resulting in the removal of 9 patients and 10 lesions. DM was defined based on documented diagnosis in hospital medical records or confirmation by the referring general practitioner. No distinction was made based on glycemic control or treatment modality at baseline. Subgroup classification into type 1 and type 2 diabetes was based on physician documentation and clinical history. The procedural approach, including lesion preparation and stenting strategy, was left to the discretion of the treating interventional cardiologist. The study protocol complied with the ethical principles of the Declaration of Helsinki and was approved by the institutional review boards of all participating centers.
Definitions and imaging analysis
All coronary angiograms were analyzed centrally at an independent core laboratory. The anatomical complexity of CAD was quantified using the synergy between PCI with taxus and cardiac surgery (SYNTAX) score, provided that adequate visualization of the major epicardial vessels was available. The extent of CAC was assessed by the operator during the procedure using angiographic criteria and, where applicable, intracoronary imaging (ICI). The decision to perform IVL was made at the operator’s discretion, typically during the procedure after initial lesion assessment with angiography and, when available, ICI.
On angiography, CAC was graded as none/mild, moderate (calcifications visible only during the cardiac cycle before contrast injection), or severe (visible without cardiac motion, prior to contrast). Intravascular ultrasound (IVUS) was used to identify calcium as hyperechoic regions with acoustic shadowing, while optical coherence tomography-defined calcium appeared as signal-poor areas with well-delineated borders. Severe calcification was defined as a calcium arc of ≥270° on ICI. ,
Long calcified lesions were defined as a length >20 mm based on the length of the total stents. Quantitative coronary analysis (QCA) was performed both pre- and postprocedure using Medis Suite software (Medis Suite 4.0.24.4; Medis Medical Imaging System BV, Leiden, The Netherlands), measuring minimum lumen diameter (MLD), diameter stenosis (DS), area stenosis (AS), and reference vessel diameter (RVD). When available, IVUS and optical coherence tomography were analyzed using QCU-CMS 4.69 (Leiden University Medical Center, Leiden, The Netherlands) for evaluation of minimum lumen area (MLA) and reference vessel area. Cumulative major adverse cardiovascular events (MACE) were defined as the occurrence of one or more events within 1 year, with each patient counted only once, regardless of the number or timing of events.
Study endpoints
The primary outcome of interest was the incidence of major adverse cardiovascular events (MACE) at 1- and 2-year follow-up, defined as a composite of cardiovascular death, nonfatal myocardial infarction (MI), or clinically indicated target vessel revascularization (TVR).
Secondary outcomes included procedural success, device success, and technical success. Procedural success was defined as achieving final TIMI 3 flow with residual DS < 30% and absence of in-hospital MACE. Device success was defined as successful employment of the IVL-catheter to the target lesion and delivery of IVL pulses without direct angiographic complications. Technical success was defined by final TIMI 3 flow and residual DS < 30%, regardless of clinical events.
Additional secondary outcomes included all-cause mortality at 1 and 2 years, as well as periprocedural complications such as coronary dissection, perforation, abrupt vessel closure, no-reflow, hemodynamic instability, and cardiopulmonary resuscitation.
Statistical analysis
Continuous variables were reported as mean ± standard deviation or median with interquartile range (IQR), depending on their distribution assessed by visual inspection of histograms. Comparisons between patients with and without DM were conducted using the unpaired t test or the Mann–Whitney U test, as appropriate.
Categorical data were presented as counts with percentages and compared using the Chi-square test or Fisher’s exact test. Kaplan–Meier curves were generated to evaluate time-to-event outcomes, and survival distributions were compared using the log-rank test. Univariable logistic regression was used to evaluate associations between baseline and procedural variables and all-cause mortality. Only variables that showed a statistically significant association in univariable analysis were included in the multivariable model. Given the number of mortality events ( n = 80), the number of covariates was limited to four in order to avoid model overfitting. All analyses were performed using SPSS Statistics version 25.0 (IBM Corp., Armonk, NY). A two-sided p value <0.05 was considered statistically significant.
Results
Baseline characteristics
A total of 574 patients were included in the study, of whom 193 (33.6%) had DM and 381 (66.4%) did not. Patients with DM had a higher body mass index (27.29 [24.40 to 30.73] vs 26.22 [23.57 to 28.72]; p = 0.022) and lower estimated glomerular filtration rate (eGFR) (65 [47 to 82.25] vs 73 [55 to 85.25] ml/min; p = 0.007). Hypertension ( n = 156, 80.8% vs n = 255, 66.9%; p < 0.001) and dyslipidemia ( n = 118, 61.1% vs n = 196, 51.4%; p = 0.015) were more common in patients with diabetes.
There was no significant difference in age (73.0 ± 8.0 vs 72.8 ± 9.5 years; p = 0.781) or sex distribution (males: n = 140, 72.5% vs n = 281, 73.8%; p = 0.718) between the two groups. The SYNTAX score (19 [12 to 29]; p = 0.401), degree of fluoroscopic calcification (p = 0.838), and left ventricular ejection fraction categories (p = 0.891) were also similar between groups. A history of MI was more prevalent in patients with diabetes ( n = 88, 45.6% vs n = 120, 31.5%; p < 0.001), while rates of previous PCI and coronary artery bypass graft surgery did not differ significantly (see Table 1 for full baseline characteristics).
Table 1
Baseline demographics and medical history per group
|
Overall
N = 574 |
Nondiabetic
N = 381 |
Diabetic
N = 193 |
p value | |
|---|---|---|---|---|
| Age, years | 72.89 ± 9.02 | 72.82 ± 9.52 | 73.03 ± 7.95 | 0.781 |
| Male, n (%) | 421 (73.3%) | 281 (73.8%) | 140 (72.5%) | 0.718 |
| BMI | 26.53 [23.81-29.34] | 26.22 [23.57-28.72] | 27.29 [24.40-30.73] | 0.022 |
| eGFR, ml/min | 71 [53-85] | 73 [55-85.25] | 65 [47-82.25] | 0.007 |
| History of smoking, n (%) | 240 (41.8%) | 157 (41.2%) | 83 (43%) | 0.582 |
| Diabetes mellitus type 1, n (%) | 15 (2.6%) | – | 15 (7.8%) | – |
| Diabetes mellitus type 2, n (%) | 146 (25.4%) | – | 146 (75.6%) | – |
| Hypertension, n (%) | 411 (71.6%) | 255 (66.9%) | 156 (80.8%) | <0.001 |
| Dyslipidemia, n (%) | 314 (54.7%) | 196 (51.4%) | 118 (61.1%) | 0.015 |
| SYNTAX score | 19 [12-29] | 19 [12-28] | 20 [11.5-30.5] | 0.401 |
| Fluoroscopic calcification | 0.838 | |||
| Not possible, n (%) | 48 (8.4%) | 30 (7.9%) | 18 (9.3%) | |
| None/mild, n (%) | 33 (5.8%) | 21 (5.5%) | 12 (6.2%) | |
| Moderate, n (%) | 80 (13.9%) | 54 (14.2%) | 26 (13.5%) | |
| Severe, n (%) | 272 (47.4%) | 186 (48.8%) | 86 (44.6%) | |
| Left ventricular ejection fraction* | 0.891 | |||
| Good (>50%), n (%) | 303 (52.8%) | 205 (53.8%) | 98 (50.8%) | |
| Reasonable (30-50%), n (%) | 112 (19.5%) | 76 (19.9%) | 36 (18.7%) | |
| Poor (20-30%), n (%) | 23 (4.0%) | 17 (4.5%) | 6 (3.1%) | |
| Very poor (<20%), n (%) | 4 (0.7%) | 3 (0.8%) | 1 (0.5%) | |
| Unknown, n (%) | 17 (3.0%) | 10 (2.6%) | 7 (3.6%) | |
| Previous MI, n (%) | 208 (36.2%) | 120 (31.5%) | 88 (45.6%) | <0.001 |
| Previous PCI, n (%) | 263 (45.8%) | 167 (43.8%) | 96 (49.7%) | 0.170 |
| Previous CABG, n (%) | 105 (18.3%) | 69 (18.1%) | 36 (18.7%) | 0.863 |
BMI = body mass index; CABG = coronary artery bypass graft surgery; eGFR = estimated glomerular filtration rate; ICI = intracoronary imaging; MI = myocardial infarction; PCI = percutaneous coronary intervention; SYNTAX = Synergy between PCI with Taxus and Cardiac Surgery.
*Fisher-Freeman-Halton exact test.
Lesion and procedural characteristics
Target vessel distribution, lesion characteristics, use of ICI, and application of additional plaque modification techniques were comparable between diabetic and nondiabetic patients ( Table 2 ). The LAD was the most frequently treated vessel in both groups ( n = 83, 40.5% vs n = 186, 46.9%; p = 0.137), and bifurcation lesions occurred at similar rates ( n = 37, 18.0% vs n = 98, 24.7%; p = 0.064). The use of ICI after IVL was borderline significantly lower in the diabetes group (IVUS: n = 61, 29.8% vs n = 150, 37.8%; p = 0.050).
Table 2
Lesion and procedural characteristics
| Overall N = 602 |
Nondiabetic
N = 397 |
Diabetic
N = 205 |
p value | |
|---|---|---|---|---|
| Target vessel | ||||
| LM, n (%) | 65 (10.8%) | 49 (12.3%) | 16 (7.8%) | 0.09 |
| LAD, n (%) | 269 (44.7%) | 186 (46.9%) | 83 (40.5%) | 0.137 |
| LCx, n (%) | 97 (16.1%) | 61 (15.4%) | 36 (17.6%) | 0.487 |
| RCA, n (%) | 211 (35.1%) | 132 (33.2%) | 79 (38.5%) | 0.198 |
| Lesion characteristics | ||||
| Bifurcation, n (%) | 135 (22.4%) | 98 (24.7%) | 37 (18.0%) | 0.064 |
| Aorta-ostial, n (%) | 147 (24.4%) | 104 (26.2%) | 43 (21.0%) | 0.158 |
| CTO, n (%) | 45 (7.5%) | 30 (7.6%) | 15 (7.3%) | 0.916 |
| Long segment, n (%) | 390 (64.8%) | 253 (63.7%) | 137 (66.8%) | 0.450 |
| In-stent, n (%) | 184 (30.6%) | 118 (29.7%) | 66 (32.2%) | 0.533 |
| IVL | ||||
| IVL balloon maximum diameter, mm | 3.5 [3-4] | 3.5 [3.0-4.0] | 3.5 [3.0-4.0] | 0.605 |
| Number of pulses, n (%) | 80 [60-80] | 80 [60-80] | 80 [60-80] | 0.984 |
| Predilatation, n (%) | 493 (81.9%) | 324 (81.6%) | 169 (82.4%) | 0.142 |
| Balloon size predilatation, mm | 3 [2.5-3.5] | 3.0 [2.5-3.5] | 3.0 [2.75-3.5] | 0.923 |
| Postdilatation, n (%) | 496 (82.4%) | 325 (81.9%) | 171 (83.4%) | 0.067 |
| Balloon size postdilatation, mm | 3.5 [3.5-4.0] | 4.0 [3.5-4.0] | 3.5 [3.5-4.0] | 0.004 |
| After stenting (bail out), n (%) | 81 (13.5%) | 53 (13.4%) | 28 (13.7%) | 0.916 |
| ICI | 289 (48%) | 193 (48.6%) | 96 (46.8%) | 0.737 |
| Pre-IVL ICI, n (%) | 220 (36.5%) | 149 (37.5%) | 71 (34.6%) | 0.484 |
| IVUS, n (%) | 197 (32.7%) | 136 (34.3%) | 61 (29.8%) | 0.265 |
| OCT, n (%) | 25 (4.2%) | 14 (3.5%) | 11 (5.4%) | 0.284 |
| Post-IVL ICI, n (%) | 238 (39.5%) | 164 (41.3%) | 74 (36.1%) | 0.215 |
| IVUS, n (%) | 211 (35.1%) | 150 (37.8%) | 61 (29.8%) | 0.050 |
| OCT, n (%) | 24 (4%) | 13 (3.3%) | 11 (5.4%) | 0.214 |
| Other plaque modification technique used | ||||
| RA (pre), n (%) | 75 (12.5%) | 56 (14.1%) | 19 (9.3%) | 0.089 |
| Cutting balloon (pre), n (%) | 5 (0.8%) | 4 (1.0%) | 1 (0.5%) | 0.666 * |
| OPN balloon (pre), n (%) | 1 (0.2%) | 1 (0.3%) | 0 (0.0%) | 1.000 * |
| RA (post), n (%) | 5 (0.8%) | 2 (0.5%) | 3 (1.5%) | 0.344 * |
| Cutting balloon (post), n (%) | 0 | 1 (0.3%) | 1 (0.5%) | 0.341 * |
| OPN balloon (post), n (%) | 3 (0.5%) | 2 (0.5%) | 1 (0.5%) | 1.000 * |
| Treatment after IVL | ||||
| Stent implantation, n (%) | 467 (77.6%) | 310 (78.1%) | 157 (76.6%) | 0.676 |
| Stent diameter, mm | 3.5 [3.5-4.0] | 3.5 [3.5-4.0] | 3.5 [3.5-4.0] | 0.042 |
| Drug-coated balloon, n (%) | 46 (7.6%) | 30 (7.6%) | 16 (7.8%) | 0.913 |
| Plain old balloon, n (%) | 303 (50.3%) | 266 (67%) | 138 (67.3%) | 0.938 |
| Procedural time, min [IQR] | 81 [59-110.75] | 81 [58.25-109] | 80.5 [60-115] | 0.434 |
| Fluoroscopy time, min [IQR] | 23.3 [16-36] | 23 [16-36] | 24 [16-36] | 0.883 |
| Contrast volume, ml [IQR] | 170 ± 75.95 | 170 ± 75.73 | 165 ± 76.60 | 0.744 |
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