Abstract
Background
Patients undergoing dialysis have a significant risk of peripheral artery disease, limb amputation, and mortality. Paclitaxel‐coated devices (PCDs) are used to reduce restenosis after endovascular therapy, but their safety and efficacy in a dialysis‐dependent population remain unclear. We aimed to evaluate the association between PCDs and major clinical outcomes in patients with maintenance dialysis undergoing endovascular therapy for symptomatic peripheral artery disease.
Methods
We conducted a nationwide retrospective cohort analysis using the National Health Insurance Research Database in Taiwan. Patients under dialysis receiving endovascular therapy between May 2016 and December 2022 were included. Patients were categorized into PCD and non‐PCD groups during the index procedure. Propensity score matching was performed to balance baseline characteristics. The primary outcome was defined as the composite of lower limb amputation or all‐cause mortality. Cardiovascular outcomes and clinical‐driven reintervention were secondary outcomes.
Results
Among 10 235 eligible patients, 1169 (11.4%) received PCDs. After 1:3 matching, 1160 and 3480 patients in the PCD and non‐PCD groups were analyzed. PCD use was associated with a significantly lower risk of the primary outcome (47.6% versus 52.2%; hazard ratio [HR], 0.85 [95% CI, 0.77–0.93]). Risks of amputation (20.7% versus 23.8%; subdistribution HR, 0.84 [95% CI, 0.73–0.97]) and all‐cause mortality (35.9% versus 38.9%; HR, 0.87 [95% CI, 0.78–0.97]) were also significantly lower with PCD use. Cardiovascular outcomes and clinical‐driven reintervention were similar between groups.
Conclusions
Use of PCD in dialysis‐dependent patients undergoing endovascular therapy for peripheral artery disease was associated with reduced risk of the composite outcome of amputation and all‐cause mortality.
Keywords: all‐cause mortality, composite cardiovascular outcome, composite limb outcome, dialysis, paclitaxel‐coated device, peripheral endovascular intervention
Subject Categories: Peripheral Vascular Disease
Nonstandard Abbreviations and Acronyms
- CLTI
chronic limb‐threatening ischemia
- MACE
major adverse cardiovascular event
- NHI
National Health Insurance
- NHIRD
National Health Insurance Research Database
- PCD
paclitaxel‐coated device
- SHR
subdistribution hazard ratio
Clinical Perspective.
What Is New?
In this nationwide retrospective cohort study of >10 000 dialysis‐dependent patients undergoing endovascular therapy for peripheral artery disease, the use of paclitaxel‐coated devices was associated with a significantly lower risk of the composite end point of major limb amputation or all‐cause mortality compared with non–drug‐coated devices.
What Are the Clinical Implications?
These findings suggest that paclitaxel‐coated devices are not only safe in the high‐risk dialysis population but may also provide a protective benefit for amputation and overall survival, supporting their use in interventional strategies for patients with end‐stage renal disease with symptomatic peripheral artery disease.
Peripheral artery disease (PAD) is a prevalent and serious comorbidity in patients with chronic kidney disease. Patients on maintenance dialysis are 4 to 6 times more likely to develop PAD than counterparts with preserved renal function. 1 Advanced chronic kidney disease significantly increases the risk of major amputation or PAD‐related death after revascularization in patients with chronic limb‐threatening ischemia (CLTI). 2 Compared with those with milder stages, patients with stage 3 to 4 chronic kidney disease have nearly a 50% higher risk of major amputation or all‐cause mortality. End‐stage renal disease or dialysis dependence is associated with a 3‐fold increase in overall mortality and major adverse cardiovascular events (MACEs), and double the risk of major amputation. 3 These findings underscore that in a dialysis‐dependent population, PAD represents more than a localized threat to limb viability; rather, it serves as a critical marker of systemic atherosclerotic burden and greater cardiovascular risk.
Endovascular interventions using paclitaxel‐coated devices (PCDs), which include paclitaxel‐coated balloons and paclitaxel‐eluting stents, have become integral to PAD treatment. High‐quality randomized controlled trials and registries have validated their efficacy in reducing restenosis and repeat interventions, compared with noncoated balloons or bare‐metal stents. 4 , 5 Moreover, recent meta‐analyses and real‐world studies have found no evidence that PCDs increase long‐term mortality. 6 , 7 , 8 Despite these advancements, therapeutic strategies for high‐risk patients with multiple comorbidities remain nuanced. Although PCD treatment in patients with diabetes shows similar 5‐year reintervention rates to those without diabetes, these patients continue to face significantly higher all‐cause mortality. 9 , 10 Furthermore, the BASIL‐3 (Bypass versus Angioplasty in Severe Ischaemia of the Leg‐3) trial showed that PCD may not confer significant clinical benefits in amputation and overall survival over plain balloon angioplasty in CLTI. 11 Other factors, such as biological sex and age‐related physiological changes, further complicate the treatment landscape, as certain subgroups remain consistently underdiagnosed or exhibit disparities in their response to endovascular therapy. 12
Of particular relevance, dialysis patients are often underrepresented or excluded from key PCD trials and registries, leaving a critical evidence gap on PCD effectiveness and safety in this exceptionally high‐risk group. 3 , 13 , 14 Most available data on PCD use in a dialysis population focus on arteriovenous grafts or access stenosis, with limited insight into lower limb outcomes or survival. 15 To address this gap, our study sought to investigate the clinical effectiveness and safety of PCDs on all‐cause mortality, limb‐related outcomes, and cardiovascular events in dialysis‐dependent patients with PAD, leveraging the largest nationwide medical database in Taiwan.
METHODS
The data underlying this article will be shared on reasonable request to the corresponding author.
Ethics Approval and Consent to Participate
This study was approved by the Research Ethics Committee of the National Taiwan University Hospital (NTUH‐REC No.: 202202020W; and date of approval: March 4, 2022). The informed consent could be waived because the original identification numbers of the patients have been encrypted in the National Health Insurance Research Database (NHIRD).
Data Source
Taiwan's National Health Insurance (NHI) program has been in place since 1995 and was established to deliver comprehensive health care coverage to the entire population. Currently, the NHI system insures ≈99.5% of Taiwan's 23.74 million residents. NHI‐related data are maintained by the Health and Welfare Data Science Center as the NHIRD, which adheres to stringent confidentiality protocols, releasing information solely after ethical approval has been granted. Formally approved under the National Health Informatics Project, longitudinal records from 2000 to 2022 were used for this study. The present study used the integrated medical and pharmacy claims data within the NHIRD, and the required documentation and coding procedures are governed by standardized regulations. Additional details on the NHIRD have been published previously. 16
Study Population and Paclitaxel Exposure
After paclitaxel‐coated devices (PCDs) became reimbursable under Taiwan's NHI on May 1, 2016, we identified dialysis‐dependent patients with symptomatic PAD who underwent endovascular revascularization through December 31, 2022. Maintenance dialysis status was confirmed by possession of a Catastrophic Illness Certificate for end‐stage kidney disease. This includes subjects with claudication or with CLTI. For individuals who underwent >1 endovascular intervention during the study period, the first intervention was defined as the index procedure. Patients were then classified into PCD or non‐PCD cohorts according to the devices used at the index procedure. Patients were excluded if demographic information was missing, age was <20 years, in‐hospital death occurred during the index admission, or follow‐up was <3 months. The exposure of interest was use of PCDs. The PCD cohort included patients treated with paclitaxel‐eluting stents, paclitaxel‐coated balloons, or both, whereas the non‐PCD cohort comprised those treated with bare‐metal stents, plain balloon percutaneous transluminal angioplasty, or both. Only devices approved by the Taiwan Food and Drug Administration were eligible in our study (Table S1).
Covariates
Baseline covariates were obtained from the NHIRD and included age, sex, residential urbanization level, dialysis modality, and dialysis vintage (duration). PAD presentation was categorized as claudication or CLTI. We further ascertained prior lower‐limb and coronary revascularization, prior lower‐limb amputation, baseline comorbidities, Charlson Comorbidity Index scores, prior clinical events, and concomitant medication use. Dialysis vintage was derived from the Catastrophic Illness Certificate database, which contains records dating back to the inception of the NHIRD in March 1995. Comorbidities, such as hypertension, diabetes, atrial fibrillation, dyslipidemia, chronic kidney disease, chronic obstructive pulmonary disease, and malignancy, were defined using at least 2 outpatient claims or 1 inpatient diagnosis to ensure diagnostic validity. Prior cardiovascular events, including myocardial infarction (MI), heart failure hospitalization, cerebrovascular accident, and systemic thromboembolism, were identified based on inpatient diagnoses before the index date, with available records traceable back to the year 2000. Concomitant medications, including antiplatelet agents, anticoagulants, statins, and antihypertensive agents, were determined from prescriptions dispensed within the first 3 months after cohort entry. Comorbidities were identified using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD‐9‐CM), diagnostic codes before 2015 and both ICD‐9‐CM and International Classification of Diseases, Tenth Revision, Clinical Modification (ICD‐10‐CM), diagnostic codes in 2016 and thereafter (Table S2).
Outcomes
The primary outcome was a composite of lower‐limb amputation or all‐cause mortality. Secondary limb‐related outcomes included amputation, new‐onset CLTI, and clinically driven repeat revascularization (eg, endovascular therapy or peripheral bypass). Cardiovascular outcomes included cardiovascular mortality, ischemic stroke, and MI. CLTI was defined as ischemia‐related persistent rest pain involving the limb, foot, or toes, or threatened tissue loss; new‐onset CLTI was identified by ≥2 outpatient claims or ≥1 inpatient diagnosis codes. Clinically driven reintervention was defined as a target‐vessel procedure performed because of worsening clinical status after the index procedure. Amputation and reintervention events were ascertained from inpatient claims using Taiwan NHI reimbursement codes, whereas MI and ischemic stroke were identified using principal discharge diagnoses. Mortality information (date, place, and underlying cause of death) was obtained through linkage to the Taiwan Death Registry via the Health and Welfare Data Science Center. Patients were followed up from the discharge date of the index procedure until the first occurrence of the outcome of interest, death, day 730 of follow‐up, or the end of data availability (December 31, 2022), whichever came first. Because dialysis‐dependent patients with PAD typically have limited life expectancy (mean follow‐up time in our cohort, 2.08 years), we prespecified a maximum follow‐up of 2 years.
Statistical Analysis
To reduce confounding between cohorts, we performed propensity score matching. Propensity scores were derived from a multivariable logistic regression model in which treatment assignment (PCD versus non‐PCD) was modeled as a function of all baseline covariates entered simultaneously; follow‐up duration was not included, and the index admission discharge date was incorporated instead to align potential follow‐up time. We used the nearest neighbor algorithm with a caliper width of 0.2 and a random matching order, conducted without replacement. Each patient in the PCD group was matched to 3 patients in the non‐PCD group. Postmatching balance was assessed using absolute standardized mean differences, with a standardized mean difference <0.1 indicating negligible imbalance.
All outcome analyses were performed within the matched cohort. Cox proportional hazards models were used for outcomes involving death (including all‐cause mortality, MACEs, and cardiovascular death). For nonfatal outcomes, Fine–Gray subdistribution hazard models were applied with all‐cause mortality treated as the competing risk. In these time‐to‐event models, treatment group (PCD versus non‐PCD) was the only explanatory variable. Within‐pair clustering of outcomes after matching was addressed through the use of robust SEs. Prespecified subgroup analyses were conducted to explore potential treatment‐effect heterogeneity. A 2‐sided P<0.05 was considered statistically significant. All analyses, including data linkage, were conducted on site at the Health and Welfare Data Science Center using SAS version 9.4.
RESULTS
Inclusion of Patients
From May 1, 2016, to December 31, 2022, totally 39 710 patients underwent lower limb endovascular revascularization. Of whom, 12 420 dialysis patients were initially assessed for study eligibility. Among them, 16 were excluded because of incomplete demographic data or age <20 years. Additionally, 895 patients were excluded because they experienced in‐hospital mortality during the index hospitalization. A further 1274 patients were excluded because of insufficient follow‐up duration of <3 months. In the remaining 10 235 patients, 1169 (11.4%) received PCD and 9066 (88.6%) received non‐PCD treatment (bare metal stent or percutaneous transluminal angioplasty alone) (Figure 1).
Figure 1. Flowchart for patients' inclusion.
BMS indicates bare metal stent; DCB, drug‐coated balloon; DES, drug‐eluting stent; EVT, endovascular therapy; PAD, peripheral artery disease; and PCD, paclitaxel‐coated device.
Baseline Characteristics
In the overall cohort, 9804 (95.8%) patients with PAD underwent hemodialysis, and the median duration of dialysis treatment was 5.1 (interquartile range, 2.3–8.8) years. The mean±SD age was 69.8±11.0 years in the PCD group and 68.3±11.1 years in the non‐PCD group. Overall, 5565 (54.4%) patients presented with CLTI, and 4670 (45.6%) presented with intermittent claudication at the time of inclusion. A total of 564 (48.2%) of the patients treated with PCD and 5142 (56.7%) treated with non‐PCD were men. A total of 1399 (13.7%) patients had prior surgical bypass or endovascular therapy, and 1378 (13.5%) patients underwent amputation before. Among the patients with available data, 689 of 1169 (58.9%) treated with PCD and 4876 of 9066 (53.8%) treated with non‐PCD presented with CLTI at the beginning of the study. A total of 1012 of 1169 (86.6%) with PCD treatment and 7750 of 9066 (85.5%) with non‐PCD were diabetic, whereas 588 (50.3%) of the patients with PCD treatment and 3914 (43.2%) of the patients with non‐PCD were receiving statin therapy. After propensity score matching, all the baseline characteristics were well balanced between the groups, as demonstrated by all the standardized difference values being <0.1 (Table 1).
Table 1.
Baseline Characteristics of the Patients
| Variable | Total (n=10 235) | Before matching | After matching | ||||
|---|---|---|---|---|---|---|---|
| PCD (n=1169) | Non‐PCD (n=9066) | STD | PCD (n=1160) | Non‐PCD (n=3480) | STD | ||
| Age, y | 68.5±11.1 | 69.8±11.0 | 68.3±11.1 | 0.13 | 69.8±11.0 | 69.6±10.8 | 0.01 |
| Male sex | 5706 (55.7) | 564 (48.2) | 5142 (56.7) | −0.17 | 564 (48.6) | 1719 (49.4) | −0.02 |
| Urbanization level of the residence | |||||||
| Low | 1166 (11.4) | 93 (8.0) | 1073 (11.8) | −0.13 | 93 (8.0) | 281 (8.1) | <0.01 |
| Moderate | 2965 (29.0) | 317 (27.1) | 2648 (29.2) | −0.05 | 316 (27.2) | 959 (27.6) | −0.01 |
| High | 3218 (31.4) | 363 (31.1) | 2855 (31.5) | −0.01 | 363 (31.3) | 1096 (31.5) | <0.01 |
| Very high | 2886 (28.2) | 396 (33.9) | 2490 (27.5) | 0.14 | 388 (33.4) | 1144 (32.9) | 0.01 |
| Dialysis modality | |||||||
| Hemodialysis | 9804 (95.8) | 1094 (93.6) | 8710 (96.1) | −0.11 | 1090 (94.0) | 3279 (94.2) | −0.01 |
| Peritoneal dialysis | 431 (4.21) | 75 (6.4) | 356 (3.93) | 0.11 | 70 (6.0) | 201 (5.78) | 0.01 |
| Dialysis vintage, y | |||||||
| Median (interquartile range) | 5.1 (2.3–8.8) | 5.0 (2.1–8.9) | 5.1 (2.3–8.7) | NA | 5.0 (2.1–8.9) | 4.9 (2.1–8.9) | NA |
| <5 | 5030 (49.1) | 589 (50.4) | 4441 (49.0) | 0.03 | 585 (50.4) | 1776 (51.0) | −0.01 |
| 5–10 | 3214 (31.4) | 332 (28.4) | 2882 (31.8) | −0.07 | 331 (28.5) | 991 (28.5) | <0.01 |
| >10 | 1991 (19.5) | 248 (21.2) | 1743 (19.2) | 0.05 | 244 (21.0) | 713 (20.5) | 0.01 |
| Presentation of PAD | |||||||
| Claudication | 4670 (45.6) | 480 (41.1) | 4190 (46.2) | −0.10 | 479 (41.3) | 1416 (40.7) | 0.01 |
| Chronic limb‐threatening ischemia | 5565 (54.4) | 689 (58.9) | 4876 (53.8) | 0.10 | 681 (58.7) | 2064 (59.3) | −0.01 |
| Previous treatment | |||||||
| Previous EVT/peripheral bypass | 1399 (13.7) | 175 (15.0) | 1224 (13.5) | 0.04 | 174 (15.0) | 522 (15.0) | <0.01 |
| Lower limb amputation | 1378 (13.5) | 140 (12.0) | 1238 (13.7) | −0.05 | 140 (12.1) | 448 (12.9) | −0.02 |
| Coronary revascularization | 4692 (45.8) | 572 (48.9) | 4120 (45.4) | 0.07 | 567 (48.9) | 1720 (49.4) | −0.01 |
| Charlson Comorbidity Index score | |||||||
| Mean±SD | 5.77±1.58 | 5.81±1.56 | 5.77±1.58 | 0.03 | 5.81±1.56 | 5.80±1.54 | <0.01 |
| ≤4 | 1843 (18.0) | 185 (15.8) | 1658 (18.3) | −0.07 | 184 (15.9) | 549 (15.8) | <0.01 |
| 5–6 | 5539 (54.1) | 651 (55.7) | 4888 (53.9) | 0.04 | 644 (55.5) | 1944 (55.9) | −0.01 |
| ≥7 | 2853 (27.9) | 333 (28.5) | 2520 (27.8) | 0.02 | 332 (28.6) | 987 (28.4) | 0.01 |
| Comorbid condition | |||||||
| Diabetes | 8762 (85.6) | 1012 (86.6) | 7750 (85.5) | 0.03 | 1004 (86.6) | 3034 (87.2) | −0.02 |
| Coronary artery disease | 6755 (66.0) | 806 (68.9) | 5949 (65.6) | 0.07 | 798 (68.8) | 2414 (69.4) | −0.01 |
| Atrial fibrillation | 1292 (12.6) | 153 (13.1) | 1139 (12.6) | 0.02 | 152 (13.1) | 456 (13.1) | <0.01 |
| Hypertension | 9556 (93.4) | 1096 (93.8) | 8460 (93.3) | 0.02 | 1088 (93.8) | 3252 (93.4) | 0.01 |
| Dyslipidemia | 4566 (44.6) | 578 (49.4) | 3988 (44.0) | 0.11 | 570 (49.1) | 1732 (49.8) | −0.01 |
| COPD | 874 (8.5) | 87 (7.4) | 787 (8.7) | −0.05 | 87 (7.5) | 258 (7.4) | <0.01 |
| Malignancy | 1083 (10.6) | 118 (10.1) | 965 (10.6) | −0.02 | 118 (10.2) | 347 (10.0) | 0.01 |
| Carotid disease | 162 (1.6) | 19 (1.6) | 143 (1.6) | <0.01 | 19 (1.6) | 54 (1.6) | 0.01 |
| History of event | |||||||
| Myocardial infarction | 3257 (31.8) | 375 (32.1) | 2882 (31.8) | 0.01 | 373 (32.2) | 1142 (32.8) | −0.01 |
| Heart failure hospitalization | 5101 (49.8) | 615 (52.6) | 4486 (49.5) | 0.06 | 611 (52.7) | 1804 (51.8) | 0.02 |
| Stroke | 1585 (15.5) | 161 (13.8) | 1424 (15.7) | −0.05 | 161 (13.9) | 505 (14.5) | −0.02 |
| Systemic thromboembolism | 2219 (21.7) | 249 (21.3) | 1970 (21.7) | −0.01 | 248 (21.4) | 739 (21.2) | <0.01 |
| Venous thromboembolism | 499 (4.9) | 43 (3.7) | 456 (5.0) | −0.07 | 43 (3.7) | 108 (3.1) | 0.03 |
| Concomitant antiplatelet agent | |||||||
| Aspirin | 6436 (62.9) | 770 (65.9) | 5666 (62.5) | 0.07 | 763 (65.8) | 2282 (65.6) | <0.01 |
| Clopidogrel | 6329 (61.8) | 897 (76.7) | 5432 (59.9) | 0.37 | 888 (76.6) | 2691 (77.3) | −0.02 |
| Ticagrelor | 458 (4.5) | 52 (4.4) | 406 (4.5) | <0.01 | 52 (4.5) | 162 (4.7) | −0.01 |
| Prasugrel | 93 (0.9) | 19 (1.6) | 74 (0.8) | 0.07 | 19 (1.6) | 27 (0.8) | 0.08 |
| Cilostazol | 7188 (70.2) | 901 (77.1) | 6287 (69.3) | 0.18 | 892 (76.9) | 2675 (76.9) | <0.01 |
| Concomitant anticoagulant | |||||||
| Vitamin K antagonist | 1077 (10.5) | 130 (11.1) | 947 (10.4) | 0.02 | 128 (11.0) | 359 (10.3) | 0.02 |
| Direct oral anticoagulants | 207 (2.0) | 25 (2.1) | 182 (2.0) | 0.01 | 25 (2.2) | 73 (2.1) | <0.01 |
| Concomitant antidiabetic medication | |||||||
| GLP1RA | 162 (1.6) | 15 (1.3) | 147 (1.6) | −0.03 | 15 (1.3) | 50 (1.4) | −0.01 |
| Other OHA | 5728 (56.0) | 674 (57.7) | 5054 (55.7) | 0.04 | 668 (57.6) | 2026 (58.2) | −0.01 |
| Insulin | 3934 (38.4) | 468 (40.0) | 3466 (38.2) | 0.04 | 464 (40.0) | 1384 (39.8) | <0.01 |
| Concomitant other medication | |||||||
| ACEi/ARB | 4745 (46.4) | 557 (47.6) | 4188 (46.2) | 0.03 | 552 (47.6) | 1662 (47.8) | <0.01 |
| β‐Blocker | 4407 (43.1) | 500 (42.8) | 3907 (43.1) | −0.01 | 495 (42.7) | 1502 (43.2) | −0.01 |
| DCCB | 5855 (57.2) | 659 (56.4) | 5196 (57.3) | −0.02 | 653 (56.3) | 1947 (55.9) | 0.01 |
| Digoxin | 207 (2.0) | 29 (2.5) | 178 (2.0) | 0.04 | 28 (2.4) | 82 (2.4) | <0.01 |
| Statin | 4502 (44.0) | 588 (50.3) | 3914 (43.2) | 0.14 | 579 (49.9) | 1736 (49.9) | <0.01 |
| NSAID/cyclooxygenase‐2 inhibitors | 6326 (61.8) | 696 (59.5) | 5630 (62.1) | −0.05 | 693 (59.7) | 2040 (58.6) | 0.02 |
| Diuretic (loop or thiazide) | 1447 (14.1) | 184 (15.7) | 1263 (13.9) | 0.05 | 183 (15.8) | 550 (15.8) | <0.01 |
| MRA | 230 (2.2) | 27 (2.3) | 203 (2.2) | <0.01 | 27 (2.3) | 90 (2.6) | −0.02 |
| Follow‐up time, y | 2.08±1.55 | 2.15±1.54 | 2.07±1.55 | 0.05 | 2.15±1.54 | 1.96±1.49 | 0.12 |
Data are presented as frequency (percentage), mean±SD, or median (interquartile range). ACEi indicates angiotensin‐converting enzyme inhibitor; ARB, angiotensin receptor blocker; COPD, chronic obstruction pulmonary disease; DCCB, dihydropyridine calcium channel blocker; EVT, endovascular therapy; GLP1RA, glucagon‐like peptide‐1 receptor agonist; MRA, mineralocorticoid receptor antagonist; OHA, oral hypoglycemic agent; PAD, peripheral artery disease; PCD, paclitaxel‐coated device; and STD, standardized difference.
Lower Limb Outcomes and All‐Cause Mortality
In the overall cohort, the mean follow‐up duration was 2.08 years. In the propensity score–matched cohort, the mean follow‐up was 2.15 years for patients treated with PCD and 1.96 years for those who were not. The primary outcome occurred in 47.6% of patients in the PCD group versus 52.2% in the non‐PCD group (hazard ratio [HR], 0.85 [95% CI, 0.77–0.93]) (Figure 2A). A total of 1069 patients (23.0%) underwent amputation, including 240 of 1160 patients (20.7%) in the PCD group and 829 of 3480 patients (23.8%) in the non‐PCD group, corresponding to a significantly lower risk of amputation in the PCD group (subdistribution HR [SHR], 0.84 [95% CI, 0.73–0.97]) (Figure 2B). Similarly, the incidence of all‐cause death was significantly lower in the PCD group (35.9%) compared with the non‐PCD group (38.9%) (HR, 0.87 [95% CI, 0.78–0.97]) (Figure 2C). The incidence of new‐onset CLTI did not differ significantly between the 2 treatment groups. Additionally, the risk of clinically driven reinterventions, via either endovascular therapy or bypass surgery, was comparable, occurring in 526 patients (45.3%) in the PCD group and 1474 patients (42.4%) in the non‐PCD group (SHR, 1.07 [95% CI, 0.97–1.18]). Furthermore, the clinical outcomes at 1‐year follow‐up were analyzed to assess the short‐term impact of treatment. Patients in the PCD group demonstrated a lower risk of all‐cause mortality and amputation at 1 year compared with those in the non‐PCD group. Notably, the incidence of clinically driven reinterventions was similar between the 2 groups during the first year (Table S3), indicating that the observed benefit of PCD was not merely a surrogate for more aggressive care.
Figure 2. Cumulative event rates of composite outcome of amputation or all‐cause death (A), lower limb amputation (B), all‐cause death (C), and major adverse cardiovascular events (D) among patients with maintenance dialysis who underwent endovascular therapy with and without using paclitaxel‐coated devices in the propensity score matched cohort.
HR indicates hazard ratio; PCD, paclitaxel‐coated device; and SHR, subdistribution HR.
Cardiovascular Outcome
During the entire follow‐up period, there were no significant differences in cardiovascular outcomes between the treatment groups. The composite outcome of cardiovascular death, ischemic stroke, or MI occurred in 319 patients (27.5%) in the PCD group and 987 patients (28.4%) in the non‐PCD group (SHR, 0.93 [95% CI, 0.82–1.06]) (Figure 2D). Cardiovascular death occurred in 233 patients (20.1%) in the PCD group compared with 730 patients (21.0%) in the non‐PCD group (HR, 0.90 [95% CI, 0.78–1.05]). There were also no significant between‐group differences in the risk of MI (SHR, 0.90 [95% CI, 0.71–1.15]) or ischemic stroke (SHR, 1.21 [95% CI, 0.87–1.70]) (Table 2).
Table 2.
Clinical Events of the Patients in the Matched Cohort
| Outcome | PCD | Non‐PCD | PCD vs non‐PCD | |
|---|---|---|---|---|
| (n=1160) | (n=3480) | HR or SHR (95% CI) | P value | |
| All‐cause death | 416 (35.9) | 1355 (38.9) | 0.87 (0.78–0.97) | 0.011 |
| Lower extremity outcome | ||||
| Lower limb amputation | 240 (20.7) | 829 (23.8) | 0.84 (0.73–0.97) | 0.017 |
| Amputation or all‐cause death | 552 (47.6) | 1817 (52.2) | 0.85 (0.77–0.93) | 0.001 |
| New onset of CLTI | 490 (42.2) | 1504 (43.2) | 0.95 (0.86–1.05) | 0.295 |
| Clinically driven reinterventions | 526 (45.3) | 1474 (42.4) | 1.07 (0.97–1.18) | 0.178 |
| Endovascular therapy | 522 (45.0) | 1448 (41.6) | 1.08 (0.98–1.20) | 0.111 |
| Peripheral bypass | 48 (4.1) | 145 (4.2) | 0.98 (0.71–1.36) | 0.923 |
| Cardiovascular outcome | ||||
| Major adverse cardiovascular events | 319 (27.5) | 987 (28.4) | 0.93 (0.82–1.06) | 0.294 |
| Myocardial infarction | 87 (7.5) | 285 (8.2) | 0.90 (0.71–1.15) | 0.387 |
| Ischemic stroke | 47 (4.1) | 115 (3.3) | 1.21 (0.87–1.70) | 0.259 |
| Cardiovascular death | 233 (20.1) | 730 (21.0) | 0.90 (0.78–1.05) | 0.175 |
Data are presented as frequency (percentage), unless specified. CLTI indicates chronic limb‐threatening ischemia; HR, hazard ratio; PCD, paclitaxel‐coated device; and SHR, subdistribution HR.
Subgroup Analysis
Results of the subgroup analyses for the primary outcome are summarized in Figure 3. Significant interactions were observed for sex, history of revascularization, CAD, and prior MI (all P for interaction <0.05). Specifically, the clinical benefit of PCD treatment was more pronounced in patients who were women, patients who had a history of revascularization (endovascular therapy or bypass), and those without CAD or prior MI. Similarly, the reduction in amputation risk was specifically enhanced among patients with a history of surgical bypass or prior endovascular therapy (Figure S1). For all‐cause mortality, the benefits of PCD were more pronounced in subgroups without CAD and those receiving cilostazol (Figure S2).
Figure 3. Subgroup analysis of the primary outcome (composite outcome of amputation or all‐cause death) in the propensity score–matched cohort.
CCI indicates Charlson comorbidity index; CLTI, chronic limb‐threatening ischemia; EVT, endovascular therapy; HD, hemodialysis; HR, hazard ratio; PCD, paclitaxel‐coated device; PCI, percutaneous coronary intervention; and PD, peritoneal dialysis.
DISCUSSION
In this large, nationwide, population‐based study of dialysis‐dependent patients with PAD, the use of PCD was associated with a significant reduction in both amputation and all‐cause death compared with non‐PCD interventions. These findings are consistent with and expand on previous observational data, supporting the clinical utility of paclitaxel‐based therapies in reducing limb‐related complications among patients undergoing dialysis, a population often excluded or underrepresented in pivotal trials of PCDs. Furthermore, our study showed PCD use was not associated with an increased risk of MACEs, thereby reinforcing the safety of PCD use. The absence of excess cardiovascular risk following PCD use further corroborates evidence from recent studies, 8 , 17 , 18 indicating that paclitaxel‐coated balloons and stents do not confer elevated mortality or cardiovascular risk, even in patients under dialysis.
The observed 16% risk reduction in major amputation suggests a limb salvage benefit consistent with previous reports. Notably, a large multicenter retrospective study similarly demonstrated reduced amputation rates and improved survival in patients with CLTI treated with PCDs, including those with renal failure. 8 , 19 Our findings complement these results by specifically focusing on patients under maintenance dialysis, a subgroup with particularly poor vascular outcomes. The association of PCD use with reduced all‐cause mortality adds to a growing body of real‐world evidence that challenges earlier concerns about paclitaxel‐associated late mortality. The initial meta‐analysis by Katsanos et al 20 raised safety concerns by suggesting increased long‐term mortality with PCD, but subsequent reanalyses revealed a smaller effect size and highlighted important methodological limitations, including missing data and heterogeneity across trials. 7 , 21 , 22 Moreover, these trials predominantly enrolled patients with intermittent claudication and limited lesion burden, and renal insufficiency was uncommon. In contrast, our study evaluated patients with advanced comorbidities and a high prevalence of CLTI, thereby addressing a critical evidence gap. Moreover, no significant differences were observed with respect to MACEs, nonfatal ischemic stroke, or MI between the PCD and non‐PCD groups, reinforcing its cardiovascular safety in patients under dialysis. The absence of excess cardiovascular risk aligns with recent registry‐based studies and large administrative claims data that failed to demonstrate a signal for cardiovascular harm associated with paclitaxel exposure. 8 , 23 , 24 , 25 , 26 This finding is of particular importance given the high competing risk of cardiovascular mortality among dialysis‐dependent patients. Nevertheless, we acknowledged that the use of PCD in a minority of the study population may reflect certain selection biases. The administration of PCD could be a marker for a higher level of specialized care or greater anatomic lesion complexity. If use of PCD is associated with superior institutional resources and comprehensive postprocedural care, the efficacy of PCD might be overestimated. However, it is equally plausible that clinicians reserved PCD for more anatomically complex or refractory lesions, which could lead to an underestimation of its efficacy compared with non‐PCD treatments. Although our analysis adjusted for a wide range of clinical variables, the influence of these unmeasured lesion anatomic complexity and institutional factors remains a limitation inherent to the observational nature of this national cohort.
Although PCDs may not directly prevent progression to CLTI or reduce the need for repeat interventions in dialysis‐dependent patients, their antiproliferative effects may enhance microvascular healing and wound resolution, thereby indirectly contributing to lower amputation rates. This observation raises important considerations about the underlying mechanisms of benefit. 27 First, the antiproliferative effect of paclitaxel may reduce perivascular inflammation and neointimal hyperplasia, both of which are prominent in dialysis patients with vascular calcification and medial sclerosis. Second, although the degree of patency maintenance may be modest in dialysis patients, PCD may still help preserve vessel openness rather than completely prevent restenosis. This level of patency may be sufficient to facilitate wound healing and reduce downstream ischemic complications, particularly when distal runoff remains adequate, thereby preserving limb perfusion even in cases where reintervention is eventually required. A multicenter prospective study conducted in Japan evaluated the outcomes of drug‐coated balloons for femoropopliteal lesions in patients undergoing hemodialysis. 28 Yamauchi et al reported a 3‐year freedom from restenosis rate of 61.9% in hemodialysis patients, suggesting that a drug‐coated balloon is a feasible treatment in this specific population. They further identified several anatomic factors independently associated with increased restenosis risk after drug‐coated balloon treatment, including absence of below‐the‐knee runoff, involvement of the popliteal artery, and severe vascular calcification and dissection. These features may indicate subgroups of hemodialysis patients who could particularly benefit from early and aggressive revascularization after a drug‐coated balloon. In our analysis, we extended the evidence by investigating not only paclitaxel‐coated balloons but also paclitaxel‐eluting stents as part of peripheral endovascular interventions. This broader approach offers a more comprehensive evaluation of PCD‐based therapies and contributes further insight into optimizing revascularization strategies for dialysis patients with PAD.
A notable finding from the subgroup analysis was the more pronounced treatment effect observed in female patients. This is particularly relevant given that women have been historically underrepresented in landmark trials, such as BASIL‐2, BASIL‐3, and BEST‐CLI (Best Endovascular Versus Best Surgical Therapy in Patients With Critical Limb Threatening Ischemia), where female enrollment ranged only between 19% and 35%. 11 , 29 , 30 Emerging evidence indicates that women often present with more severe clinical disease, increased inflammation, and higher platelet reactivity. 12 Although BEST‐CLI suggests superior outcomes with bypass surgery in women, our results demonstrate that PCD serves as a comparable alternative for this high‐risk group. Furthermore, PCD demonstrated an enhanced treatment effect in patients with prior revascularization. This finding provides essential real‐world context when compared with the BASIL‐3 trial, which reported no benefit for PCD in primary revascularization. In contrast, our results align with the IN.PACT Global study, suggesting that the antiproliferative properties of PCD remain crucial for managing the complex or recurrent lesions encountered in real‐world practice. 13 Finally, the improved survival observed in patients without CAD or those receiving cilostazol emphasizes the importance of multidisciplinary management. The higher all‐cause mortality seen in patients with concomitant CAD reflects the extensive burden of atherosclerosis, consistent with the 5‐year results of the IN.PACT Global study, where all‐cause mortality reached 23.8% in diabetic cohorts and 37.4% in CLTI cohorts. 9 Overall, these findings suggest that PCD facilitates a more tailored revascularization approach for high‐risk subgroups. However, these results should be interpreted with caution because of the limited statistical power of the subgroup analysis, and they warrant validation in larger, adequately powered prospective cohorts.
Several limitations of our study warrant consideration. First, despite rigorous propensity adjustment, residual confounding factors cannot be entirely excluded. Second, data on lesion characteristics and procedural complexity were unavailable in this database. Third, detailed information on PCD device was lacking, and variations in paclitaxel dose or excipient formulation may have influenced outcomes. Finally, as with all observational studies, causal relationships cannot be definitively established, and the findings should be interpreted in the context of the inherent limitations of administrative coding.
Conclusions
Among dialysis‐dependent patients with PAD, PCD use was associated with significantly improved limb salvage and overall survival, with a comparable safety profile for MACEs. These findings support the broader application of the PCD‐based approach to optimize outcomes in dialysis patients, who represent the most vulnerable population at risk for treatment failure and limb loss.
Sources of Funding
This research was supported by the Ministry of Science and Technology of Taiwan (MOST 108‐2221‐E‐002‐163 and MOST 109‐2221‐E‐002‐083) and National Taiwan University Hospital (107‐EDN11, 108‐N4406, 108EDN02, 109‐O20, 109‐S4579, and 109‐EDN11).
Disclosures
None.
Supporting information
Tables S1–S3
Figures S1–S2
STROBE Statement—Checklist
Acknowledgments
We thank Alfred Hsing‐Fen Lin and Jia‐Kai Wu, who served in Raising Statistics Consultant Inc, for their assistance with the statistical analysis during the completion of the manuscript. We thank the staff of the Department of Medical Research at National Taiwan University Hospital for the integrated medical database. We thank the staff of the Third Core Lab, Department of Medical Research, National Taiwan University Hospital, for technical support during the study. Generative AI and AI‐assisted technologies were NOT used in the preparation of this work.
Author contributions: Conceptualization: C.‐Y.H., J.‐K.L., H.‐P.W., W.‐J.C., S.‐K.H., S.‐H.L. P.‐C.H., C.‐C.C., C.‐H.H., and H.‐L.H.; methods: C.‐Y.H., J.‐K.L., C.‐H.H., and H.‐L.H.; software: J.‐K.L.; validation: C.‐Y.H. and J.‐K.L.; formal analysis: J.‐K.L.; investigation: C.‐Y.H. and J.‐K.L.; resources: H.‐P.W., W.‐J.C., S.‐K.H., P.‐C.H., and C.‐C.C.; data curation: C.‐Y.H. and J.‐K.L.; writing (original draft preparation): C.‐Y.H.; writing (review and editing): C.‐Y.H. and J.‐K.L.; visualization: C.‐Y.H. and J.‐K.L.; supervision: J.‐K.L.; project administration: C.‐Y.H., J.‐K.L., C.‐H.H., and H.‐L.H. All authors have read and agreed to the published version of the manuscript.
This manuscript was sent to Olufunmilayo H. Obisesan, MD, MPH, Assistant Editor, for review by expert referees, editorial decision, and final disposition.
Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/JAHA.126.050231
For Sources of Funding and Disclosures, see page 12.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Tables S1–S3
Figures S1–S2
STROBE Statement—Checklist