Abstract
Background
Women with chronic limb-threatening ischemia remain historically underrepresented in peripheral artery disease trials and often exhibit distinct anatomic and clinical profiles. The LIFE-BTK randomized trial demonstrated superiority of an everolimus-eluting resorbable scaffold (DRS) over percutaneous transluminal angioplasty (PTA) for below-the-knee revascularization. This analysis assessed whether sex influenced baseline characteristics, procedural details, or clinical outcomes after DRS compared with PTA.
Methods
LIFE-BTK randomly assigned 261 patients (2:1 DRS/PTA) with Rutherford-Becker class 4-5 ischemia across 50 global sites. Sex-stratified outcomes at 1 and 2 years were evaluated using descriptive statistics, multivariate models, and Kaplan–Meier estimates. The primary efficacy end point was freedom from above-ankle amputation, target vessel occlusion, clinically-driven target lesion revascularization (CD-TLR), and binary restenosis. The primary safety end point was freedom from major adverse limb events and perioperative death. Both end points are presented here as event rates.
Results
Female patients (32% of cohort) were older and had smaller reference vessel diameters and lower ankle-brachial index values; male patients had higher tobacco use and cardiovascular comorbidities. At 1 year, DRS significantly reduced event rates for the primary efficacy end point vs PTA in both sexes (female: 23.5% vs 57.1%; male: 26.5% vs 56.0%). Benefits persisted at 2 years (female: 34.1% vs 68.4%; male: 40.7% vs 66.7%). Binary restenosis and CD-TLR were lower with DRS. Multivariate analysis showed sex was not significantly associated with outcomes, and no sex-by-treatment interaction was observed. Female patients demonstrated higher restenosis but lower CD-TLR rates, suggesting discordance between anatomic and clinical failure.
Conclusions
DRS provided durable benefit over PTA irrespective of sex. Although sex did not modify treatment effect, differences in vessel size, ischemia severity, and restenosis–reintervention patterns highlight the need for sex-specific surveillance and personalized below-the-knee treatment strategies.
Keywords: chronic limb-threatening ischemia, drug-eluting resorbable scaffold, patency, percutaneous transluminal angioplasty, reintervention, sex-related differences
Introduction
Endovascular therapy for chronic limb-threatening ischemia (CLTI) has evolved substantially over the past decade. Percutaneous transluminal angioplasty (PTA) has long been the standard treatment for infrapopliteal disease but is limited by recoil, dissection, and high restenosis rates that compromise long-term limb preservation.1, 2, 3 The emergence of drug-eluting resorbable scaffolds (DRS) has redefined expectations by combining temporary mechanical support with targeted antiproliferative therapy and eventual resorption, leaving the vessel free of permanent implants.3
The LIFE-BTK randomized trial established DRS as the first therapy to demonstrate sustained superiority over PTA for below-the-knee (BTK) revascularization, with significantly improved patency and reduced reintervention at both 1 and 2 years.4,5 These results confirm that DRS is not merely a short-term solution but a long-term strategy for vessel preservation in CLTI.
However, a critical question remains largely unanswered: Does sex influence outcomes after infrapopliteal endovascular therapy? Historically, women have been underrepresented in peripheral artery disease (PAD) trials6, 7, 8 and often present later, older, and with more severe ischemia than men.7,9,10 These differences extend beyond epidemiology; they encompass anatomic and biological factors such as smaller vessel caliber, distinct patterns of calcification, and differential healing responses.9,11, 12, 13, 14 Although prior studies have suggested that women may experience equivalent or even superior limb salvage compared with men,8,15 evidence is inconsistent, and virtually no randomized trial has explored sex-specific outcomes with next-generation devices such as DRS.
This analysis addresses that gap. Leveraging the LIFE-BTK trial dataset, we examine sex-related differences in baseline characteristics, procedural details, and long-term outcomes after treatment with DRS compared with PTA. By integrating these findings with contemporary literature on gender disparities in PAD management, we aim to provide insights that inform personalized therapy and optimize limb salvage strategies for all patients with CLTI.
Methods
Study design
LIFE-BTK was a multicenter, subject-blinded, randomized controlled trial at 50 sites across 6 countries comparing an everolimus-eluting resorbable scaffold (Esprit BTK System, Abbott) with PTA in patients with CLTI and infrapopliteal artery disease. Adults with Rutherford-Becker class (RBC) 4-5 and ≥70% stenosis or occlusion in the proximal two-thirds of the lower leg with at least one runoff vessel were eligible. Key exclusions included acute limb ischemia, inability to tolerate dual antiplatelet therapy, and planned atherectomy or specialty balloons for the target lesion. After successful inflow treatment and wire crossing, patients were randomly assigned 2:1 (DRS:PTA) via an electronic system. All sites had institutional review board approval and written consent from the participants. Detailed methodology has been published previously.4,16 The trial was registered at ClinicalTrials.gov under identifier NCT04227899.
Sex and gender considerations
Sex (classified as male or female) was abstracted from the medical record. Gender identity, gender-related social determinants, and diversity of sex development were not collected. Consistent with the Sex and Gender Equity in Research (SAGER) guidelines,17 sex was analyzed as a biological variable.
Study device and procedure
The Esprit BTK DRS is a fully biodegradable poly-l-lactic acid scaffold with poly-d,l-lactic acid-controlled release of everolimus (100 μg/cm2). Both polymers hydrolyze to lactic acid and are metabolized via the Krebs cycle. In the DRS arm, predilatation was required, abutted (nonoverlapping) scaffolds were preferred when multiple devices were used, and postdilatation used a 1:1 balloon-to-artery ratio without overexpansion. Maximum scaffolded length was 170 mm. PTA followed standard practice. Procedural success required <30% residual stenosis, preserved runoff, and no major angiographic complications. Analysis of angiographic images was performed by an independent core laboratory using quantitative vascular angiography to measure reference vessel diameter (RVD), lesion length, and percentage diameter stenosis. Vessel size eligibility at enrollment was determined by investigator visual assessment. Intravascular imaging (intravascular ultrasound or optical coherence tomography) was not mandated by the protocol and could be used at the investigator’s discretion; when performed, all intravascular images were submitted for core laboratory review and analysis.
Follow-up
In-person visits are scheduled at 30 days and 3, 6, and 12 months, then annually through 5 years. At 1 year, assessments included adverse events, medication changes, RBC, ankle-brachial index (ABI)/toe-brachial index (TBI) measurement, patient-reported outcomes (EQ-5D-5L, Walking Impairment Questionnaire, Peripheral Artery Questionnaire), and duplex ultrasound (DUS) for patency and binary restenosis (reviewed by a core laboratory). At 2 years (±28 days), an in-office visit included DUS of the target vessel, adverse event reporting, medication review, RBC, ABI/TBI measurement, and wound evaluation. DUS for patency and binary restenosis was performed at 30 days, 6 months, and 1, 2, and 3 years and reviewed by a core laboratory.
End point definitions
The primary efficacy end point was a composite of limb salvage and primary patency at 12 months, defined as freedom from above-ankle amputation of the index limb, total occlusion of the target vessel, binary restenosis (>50% by angiography or peak systolic velocity ratio ≥2.0 by DUS) of the target lesion, and clinically-driven target lesion revascularization (CD-TLR). The primary efficacy end point was revised during enrollment—after a prespecified blinded interim analysis—to include freedom from binary restenosis and extend follow-up from 6 to 12 months to better detect clinically meaningful differences, consistent with recent randomized trials. The combined primary safety end point was freedom from major adverse limb events and perioperative death. Major adverse limb events included above-ankle amputation and major reintervention (new bypass graft, interposition graft, thrombectomy, or thrombolysis related to the target lesion). Perioperative death was any death within 30 days of the index procedure. In this subgroup analysis, we present event rates (cumulative incidence) to illustrate differences across subgroups; end point definitions, adjudication, and time-to-event methods were unchanged from the parent study. Secondary end points included 12-month binary restenosis and a composite of freedom from above-ankle amputation, target vessel total occlusion, and CD-TLR. Additional secondary measures were procedural and clinical success, amputation-free survival, improvement in RBC, patient-reported outcomes, and cost-effectiveness analyses. Clinical end points were assessed through 5 years.
Statistical analysis
Sex-based differences at 1 and 2 years were assessed using descriptive, unadjusted analyses, multivariate adjusted models, and Kaplan–Meier (KM) estimates. Event rates were summarized as binary proportions at fixed time points and as KM curves, accounting for censoring and variable follow-up durations. Baseline and procedural comparisons were performed using t tests for continuous variables and Fisher exact test or chi-square test for categorical variables. Multivariate analyses adjusted for clinically relevant covariates to explore associations between sex and outcomes. All P values are 2-sided and informational only, and do not reflect prespecified hypothesis testing. Analyses at 2 years are descriptive and exploratory, as end points were statistically powered for the 1-year analysis only.
Results
Baseline characteristics
Among 261 randomized patients, 32% were female (Table 1). In the DRS arm (N = 173), females were older than males (76.5 vs 71.8 years, P = .005) and differed significantly by race: fewer were White (37.5% vs 65.8%, P < .001) and more declined/were unable to report race (19.6% vs 6.0%, P = .006). Hispanic ethnicity was also more common among females (26.8% vs 13.7%, P = .04). Females reported less tobacco use (32.1% vs 62.4%, P < .001) and had lower ABI values (0.80 vs 0.90, P = .04). They also had fewer index-limb wounds (37.5% vs 54.7%, P = .03) and more frequently presented with RBC 4, whereas males more often had RBC 5. Males also had numerically higher rates of cardiovascular comorbidities, including renal disease, prior myocardial infarction, and coronary revascularization. In the PTA arm (N = 88), sex differences were not statistically significant (Table 1). Age, race, ethnicity, tobacco use, and ABI were similar between groups. Trends included lower rates of congestive heart failure, fewer index-limb wounds, and less prior PAD treatment among females. Females had significantly higher total cholesterol levels compared with males (168.1 vs 141.9 mg/dL, P = .02), were more likely to receive an aspirin loading dose (18.5% vs 3.3%, P = .03) and were less likely to receive dual antiplatelet therapy loading at baseline (59.3% vs 83.6%, P = .01). Across both arms, males generally had more cardiovascular comorbidities, higher tobacco use, and more baseline wounds, whereas females had lower ABI values.
Table 1.
Key baseline characteristics for female vs. male patients within the 2 treatment arms.
| Characteristic | DRS (n = 173) |
P | PTA (n = 88) |
P-value | ||
|---|---|---|---|---|---|---|
| Female (n = 56) | Male (n = 117) | Female (n = 27) | Male (n = 61) | |||
| Age, y | 76.5 ± 10.3 (56) | 71.8 ± 9.5 (117) | .005 | 71.3 ± 10.6 (27) | 71.0 ± 10.3 (61) | .90 |
| Race | ||||||
| White | 37.5 (21/56) | 65.8 (77/117) | <.001 | 66.7 (18/27) | 62.3 (38/61) | .69 |
| Asian | 26.8 (15/56) | 17.9 (21/117) | .18 | 7.4 (2/27) | 14.8 (9/61) | .49 |
| Black or African American | 16.1 (9/56) | 10.3 (12/117) | .27 | 11.1 (3/27) | 13.1 (8/61) | >.99 |
| Declined or unable to disclose | 19.6 (11/56) | 6.0 (7/117) | .006 | 11.1 (3/27) | 6.6 (4/61) | .67 |
| Hispanic or Latino | 26.8 (15/56) | 13.7 (16/117) | .035 | 11.1 (3/27) | 14.8 (9/61) | .75 |
| Medical history | ||||||
| Tobacco use | 32.1 (18/56) | 62.4 (73/117) | <.001 | 44.4 (12/27) | 57.4 (35/61) | .26 |
| Hypertension | 91.1 (51/56) | 95.7 (112/117) | .30 | 96.3 (26/27) | 88.5 (54/61) | .43 |
| Hyperlipidemia | 78.6 (44/56) | 82.1 (96/117) | .59 | 81.5 (22/27) | 82.0 (50/61) | >.99 |
| Diabetes mellitus | 67.9 (38/56) | 72.6 (85/117) | .52 | 59.3 (16/27) | 73.8 (45/61) | .17 |
| Renal disease | 8.9 (5/56) | 19.1 (22/115) | .086 | 8.0 (2/25) | 19.7 (12/61) | .33 |
| eGFR, mL/min/1.73 m2 | 68.44 ± 26.56 (56) | 67.89 ± 22.48 (117) | .89 | 67.55 ± 18.91 (27) | 71.74 ± 28.20 (61) | .42 |
| Blood chemistry | ||||||
| Total cholesterol, mg/dL | 156.7 ± 34.7 (41) | 146.2 ± 41.0 (94) | .13 | 168.1 ± 34.1 (15) | 141.9 (± 43.3) (45) | .02 |
| LDL, mg/dL | 82.56 ± 31.26 (41) | 80.80 ± 35.27 (92) | .77 | 88.13 ± 35.35 (14) | 74.42 (± 35.69) (45) | .22 |
| Anemia | 20.0 (11/55) | 13.2 (15/114) | .25 | 4.0 (1/25) | 9.8 (6/61) | .67 |
| CHF | 17.9 (10/56) | 20.2 (23/114) | .72 | 7.4 (2/27) | 24.6 (15/61) | .060 |
| Multivessel PVD | 62.5 (35/56) | 62.5 (70/112) | >.99 | 61.5 (16/26) | 61.0 (36/59) | .96 |
| Carotid artery disease | 6.4 (3/47) | 3.1 (3/96) | .39 | 5.0 (1/20) | 4.1 (2.49) | >.99 |
| Prior MI | 13.0 (7/54) | 18.9 (20/106) | .35 | 11.1 (3/27) | 16.4 (10/61) | .75 |
| Previous PCI or CABG | 25.5 (14/55) | 39.1 (45/115) | .08 | 29.6 (8/27) | 38.3 (23/60) | .43 |
| Previous CVA | 14.3 (8/56) | 10.4 (12/115) | .46 | 18.5 (5/27) | 16.4 (10/61) | .77 |
| Baseline antithrombotic therapy | ||||||
| Subjects on chronic anticoagulant | 14.3 (8/56) | 15.4 (18/117) | .85 | 7.4 (2/27) | 9.8 (6/61) | >.99 |
| Subjects on chronic antiplatelet | 33.9 (19/56) | 33.3 (39/117) | .94 | 37.0 (10/27) | 36.1 (22/61) | .93 |
| Single antiplatelet loading dose | ||||||
| Aspirin | 5.4 (3/56) | 6.0 (7/117) | >.99 | 18.5 (5/27) | 3.3 (2/61) | .03 |
| Clopidogrel | 12.5 (7/56) | 6.0 (7/117) | .15 | 14.8 (4/27) | 8.2 (5/61) | .45 |
| DAPT loading dose | 78.6 (44/56) | 82.9 (97/117) | .49 | 59.3 (16/27) | 83.6 (51/61) | .01 |
| No loading dose | 3.6 (2/56) | 5.1 (6/117) | >.99 | 7.4 (2/27) | 4.9 (3/61) | .64 |
| Rutherford-Becker classificationa | ||||||
| 4 | 62.5 (35/56) | 47.0 (55/117) | .056 | 63.0 (17/27) | 45.9 (28/61) | .14 |
| 5 | 37.5 (21/56) | 53.0 (62/117) | .056 | 37.0 (10/27) | 54.1 (33/61) | .14 |
| Ankle-brachial index of target limb | 0.80 ± 0.26 (53) | 0.90 ± 0.34 (97) | .036 | 0.88 ± 0.24 (25) | 0.93 ± 0.37 (52) | .49 |
| Toe-brachial index of target limb | 0.57 ± 0.19 (10) | 0.50 ± 0.33 (40) | .40 | 0.47 ± 0.26 (9) | 0.45 ± 0.24 (20) | .80 |
| Wound on index limb | 37.5 (21/56) | 54.7 (64/117) | .034 | 37.0 (10/27) | 57.4 (35/61) | .078 |
| Previous amputation to index target lower limb | 8.9 (5/56) | 9.4 (11/117) | .92 | 7.4 (2/27) | 8.2 (5/61) | >.99 |
| Previous amputation to nontarget lower limb | 7.1 (4/56) | 8.5 (10/117) | >.99 | 3.7 (1/27) | 3.3 (2/61) | >.99 |
| History of treatment | 59.6 (28/47) | 56.3 (54/96) | .71 | 45.0 (9/20) | 69.4 (34/49) | .058 |
| Ipsilateral | 17.9 (5/28) | 33.3 (18/54) | 77.8 (7/9) | 29.4 (10/34) | ||
| Contralateral | 21.4 (6/28) | 20.4 (11/54) | 0 (0/9) | 14.7 (5/34) | ||
| Both | 60.7 (17/28) | 46.3 (25/54) | 22.2 (2/9) | 55.9 (19/34) | ||
Values are mean ± SD (N) or % (n/N).
CABG, coronary artery bypass graft; CHF, coronary heart failure; CVA, cerebrovascular accident; DAPT, dual antiplatelet therapy; DRS, drug-eluting resorbable scaffold; eGFR, estimated glomerular filtration rate; LDL, low-density lipoprotein; MI, myocardial infarction; PCI, percutaneous coronary intervention; PTA, percutaneous transluminal angioplasty; PVD, peripheral vascular disease.
Rutherford-Becker class 4 is ischemic rest pain, and class 5 is ischemic rest pain with minor tissue loss.
Procedural characteristics
In the DRS arm, procedure duration, inflow/nontarget lesion treatment rates, and number of target lesions were similar by sex (Table 2). Females had smaller RVD and shorter lesions. Moderate calcification was similar (29.3% vs 27.3%), whereas severe calcification occurred only in males (5.0%). Treatment of the tibioperoneal trunk–peroneal segment was more frequent in females (19.6% vs 6.0%, P = .006). Residual stenosis after predilatation was lower in females (25.3% vs 33.3%, P = .002). Final <30% stenosis was achieved in all females and in 93.9% of males. In the PTA arm, procedure time was shorter and nontarget lesions treatment rates lower in females (Table 2). Severe calcification was rare and present only in males (3.2%). Females had smaller RVD, and males tended toward more peroneal artery involvement. Across both arms, females had smaller RVD, no severe calcification, and consistently lower rates of nontarget lesion treatment, with a tendency toward less complex lesions overall.
Table 2.
Key baseline, procedural, and postprocedural lesion characteristics for female vs. male patients within the 2 treatment arms.
| Characteristic | DRS (n = 173) |
P-value | PTA (n = 88) |
P-value | ||
|---|---|---|---|---|---|---|
| Female (n = 56) | Male (n = 117) | Female (n = 27) | Male (n = 61) | |||
| Index procedure – per subject | ||||||
| Procedure time, min | 92.3 ± 59.0 (56) | 94.4 ± 43.8 (116) | .81 | 75.4 ± 36.9 (27) | 87.5 ± 57.6 (61) | .24 |
| Any inflow lesions treated | 39.3 (22/56) | 38.8 (45/116) | .95 | 44.4 (12/27) | 41.0 (25/61) | .76 |
| Nontarget lesions treated | 28.6 (16/56) | 36.8 (43/117) | .29 | 25.9 (7/27) | 42.6 (26/61) | .14 |
| Mean no. of target lesions | 1.0 ± 0.2 (56) | 1.0 ± 0.2 (116) | .81 | 1.1 ± 0.3 (27) | 1.0 ± 0.1 (61) | .29 |
| Target lesions (site reported) | ||||||
| Calcification | ||||||
| Moderate | 29.3 (17/58) | 27.3 (33/121) | .78 | 31.0 (9/29) | 27.0 (17/63) | .69 |
| Severe | 0.0 (0/58) | 5.0 (6/121) | .18 | 0.0 (0/29) | 3.2 (2/63) | >.99 |
| Target lesion characteristics (core laboratory reported) | ||||||
| Reference vessel diameter preintervention, mm | 2.84 ± 0.75 (51) | 3.00 ± 0.78 (96) | .24 | 2.60 ± 0.68 (23) | 2.92 ± 0.75 (57) | .073 |
| Lesion length, mm | 37.32 ± 29.07 (56) | 46.89 ± 32.76 (116) | .055 | 44.42 ± 32.11 (27) | 44.89 ± 27.92 (62) | .95 |
| Target lesion location | ||||||
| Anterior tibial | 37.5 (21/56) | 32.8 (38/116) | .54 | 37.0 (10/27) | 22.6 (14/62) | .16 |
| Posterior tibial | 14.3 (8/56) | 15.5 (18/116) | .83 | 7.4 (2/27) | 22.6 (14/62) | .13 |
| Peroneal | 12.5 (7/56) | 18.1 (21/116) | .35 | 11.1 (3/27) | 29.0 (18/62) | .067 |
| Tibioperoneal trunk | 8.9 (5/56) | 18.1 (21/116) | .12 | 22.2 (6/27) | 14.5 (9/62) | .37 |
| Tibioperoneal trunk–posterior tibial | 7.1 (4/56) | 9.5 (11/116) | .78 | 11.1 (3/27) | 8.1 (5/62) | .69 |
| Tibioperoneal trunk–peroneal | 19.6 (11/56) | 6.0 (7/116) | .006 | 11.1 (3/27) | 3.2 (2/62) | .16 |
| TASC II classificationa | ||||||
| A | 53.6 (30/56) | 45.7 (53/116) | .33 | 59.3 (16/27) | 50.0 (31/62) | .42 |
| B | 33.9 (19/56) | 36.2 (42/116) | .77 | 22.2 (6/27) | 27.4 (17/62) | .61 |
| C | 12.5 (7/56) | 18.1 (21/116) | .35 | 18.5 (5/27) | 22.6 (14/62) | .67 |
| % DS preintervention | 69.9 ± 20.7 (56) | 73.9 ± 17.8 (116) | .21 | 71.6 ± 20.0 (27) | 74.6 ± 21.5 (62) | .53 |
| Procedural characteristics (site reported) | ||||||
| Successful predilatation performed | 100.0 (56/56) | 100.0 (116/116) | >.99 | 100.0 (27/27) | 100.0 (61/61) | >.99 |
| Postprocedural measurements (core laboratory reported) | ||||||
| Residual % DS after predilatation | 25.3 ± 10.3 (35) | 33.3 ± 13.1 (49) | .002 | 29.0 ± NA (1) | 23.0 ± 11.3 (2) | NA |
| Postprocedural in-segment residual % DS | 15.2 ± 8.5 (56) | 18.0 ± 9.5 (114) | .054 | 21.7 ± 11.7 (26) | 23.4 ± 11.0 (58) | .53 |
| Final DS <30% | 100.0 (56/56) | 93.9 (107/114) | .10 | 73.1 (19/26) | 72.4 (42/58) | .95 |
| Residual flow-limiting dissection | 0.0 (0/56) | 0.0 (0/114) | >.99 | 0.0 (0/26) | 0.0 (0/58) | >.99 |
Values are mean ± SD (N) or % (n/N).
DRS, drug-eluting resorbable scaffold; DS, diameter stenosis; NA, not applicable; PTA, percutaneous transluminal angioplasty; TASC, TransAtlantic InterSociety Consensus.
The TASC II classification indicates the anatomical pattern of atherosclerotic disease severity. No patients had class D.
Clinical efficacy and safety outcomes
Descriptive, unadjusted analysis
Primary efficacy end point
At 1 and 2 years, event rates for the primary efficacy end point were significantly lower with DRS than with PTA in both sexes (1 year: females 23.5% vs 57.1%, P = .008; males 26.5% vs 56.0%, P = .006; 2 years: females 34.1% vs 68.4%, P = .02; males 40.7% vs 66.7%, P = .006) (Table 3). No within-arm sex differences were observed.
Table 3.
Descriptive, unadjusted analysis of clinical efficacy and safety outcomes at 1 and 2 years.
| Follow-up | Subgroup | DRS (n = 173) | P (within DRS arm) | PTA (n = 88) | P (within PTA arm) | P (between arms) | |
|---|---|---|---|---|---|---|---|
| Primary efficacy end point | 1 y | Female | 23.5 (12/51) | .69 | 57.1 (12/21) | .93 | .008 |
| Male | 26.5 (26/98) | 56.0 (28/50) | <.001 | ||||
| 2 y | Female | 34.1 (14/41) | .48 | 68.4 (13/19) | .89 | .016 | |
| Male | 40.7 (33/81) | 66.7 (30/45) | .006 | ||||
| Primary safety end point | 1 y | Female | 2.0 (1/50) | NA | 0.0 (0/26) | NA | NA |
| Male | 7.5 (8/106) | 0.0 (0/54) | NA | ||||
| 2 y | Female | 6.7 (3/45) | .45 | 4.3 (1/23) | .97 | .70 | |
| Male | 10.8 (10/93) | 4.2 (2/48) | .20 | ||||
| Target lesion binary restenosis | 1 y | Female | 23.5 (12/51) | .99 | 57.1 (12/21) | .39 | .008 |
| Male | 23.5 (23/98) | 46.0 (23/50) | .006 | ||||
| 2 y | Female | 31.7 (13/41) | .56 | 68.4 (13/19) | .27 | .010 | |
| Male | 37.0 (30/81) | 53.3 (24/45) | .078 | ||||
| Clinically-driven target lesion revascularization | 1 y | Female | 6.0 (3/50) | .69 | 3.8 (1/26) | .11 | .69 |
| Male | 7.8 (8/103) | 18.2 (10/55) | .056 | ||||
| 2 y | Female | 8.9 (4/45) | .65 | 13.0 (3/23) | .29 | .60 | |
| Male | 11.5 (10/87) | 24.0 (12/50) | .060 | ||||
| Above-ankle amputation | 1 y | Female | 0.0 (0/51) | NA | 0.0 (0/21) | NA | NA |
| Male | 4.1 (4/98) | 0.0 (0/50) | NA | ||||
| 2 y | Female | 4.9 (2/41) | .60 | 5.3 (1/19) | .53 | .95 | |
| Male | 7.4 (6/81) | 2.2 (1/45) | .25 |
Values are presented as % (n/N).
DRS, drug-eluting resorbable scaffold; NA, not applicable; PTA, percutaneous transluminal angioplasty.
Primary safety end point
Events were infrequent, with numerically higher rates in males than in females at both 1 year (DRS: 7.5% vs 2.0%; PTA: 0.0% for both) and 2 years (DRS: 10.8% vs 6.7%; PTA: 4.2% vs 4.3%) (Table 3).
Binary restenosis
At 1 year, restenosis rates were identical in DRS females and males (23.5%) but substantially higher with PTA, especially in females (57.1% vs 46.0%, P < .01 vs DRS for both) (Table 3). At 2 years, restenosis remained higher with PTA (females: 68.4% vs 31.7%, P = .01; males: 53.3% vs 37.0%, P = .08). No within-arm sex differences were observed.
CD-TLR
At 1 year, CD-TLR rates were low in females (DRS: 6.0%; PTA: 3.8%) and higher in males, particularly with PTA (DRS: 7.8%; PTA: 18.2%, P = .06) (Table 3). At 2 years, rates increased across all groups (females: 8.9% vs 13.0%; males: 11.5% vs 24.0%, P = .06). Sex differences within arms remained nonsignificant.
Above-ankle amputation
At 1 year, no female participants experienced amputation; among males, 4.1% in DRS did, while none in PTA did (Table 3). At 2 years, rates in females were similar between arms (DRS: 4.9%; PTA: 5.3%), whereas males had higher rates with DRS (7.4%) than with PTA (2.2%).
Multivariate, adjusted analysis
After covariate adjustment, sex was not significantly associated with any efficacy or safety outcome at 1 or 2 years in either treatment arm, and sex-by-treatment interaction P values were nonsignificant (Table 4).
Table 4.
Multivariate, adjusted analysis of clinical efficacy and safety outcomes at 1 and 2 years.
| Female vs male | Follow-up | DRS OR (95% CI) | P (within DRS arm) | PTA OR (95% CI) | P (within PTA arm) | P (between arms) | P interaction (between variable and arm) |
|---|---|---|---|---|---|---|---|
| Primary efficacy end point | 1 y | 0.91 (0.36, 2.25) | .83 | 1.19 (0.36, 3.98) | .77 | <.001 | .72 |
| 2 y | 0.87 (0.34, 2.20) | .76 | 1.05 (0.28, 3.99) | .94 | <.001 | .81 | |
| Primary safety end point | 1 y | 0.51 (0.05, 4.68) | .55 | NA | NA | .03 | >.99 |
| 2 y | 1.16 (0.26, 5.16) | .84 | 0.28 (<0.01, >999.99) | .98 | .18 | .99 | |
| Target lesion binary restenosis | 1 y | 1.02 (0.40, 2.58) | .97 | 2.19 (0.64, 7.47) | .21 | <.001 | .33 |
| 2 y | 0.84 (0.32, 2.17) | .72 | 2.15 (0.57, 8.18) | .26 | .003 | .26 | |
| Clinically-driven target lesion revascularization | 1 y | 1.19 (0.28, 5.15) | .82 | 0.22 (0.03, 1.93) | .17 | .11 | .21 |
| 2 y | 1.22 (0.33, 4.56) | .77 | 0.37 (0.07, 2.01) | .25 | .051 | .27 | |
| Above-ankle amputation | 1 y | <0.01 (<0.01, >999.99) | .94 | NA | NA | .31 | .96 |
| 2 y | 1.04 (0.17, 6.37) | .97 | 0.58 (<0.01, >999.99) | >.99 | .50 | >.99 |
DRS, drug-eluting resorbable scaffold; NA, not applicable; OR, odds ratio; PTA, percutaneous transluminal angioplasty.
KM analysis
Primary efficacy end point
KM curves showed consistently lower cumulative event rates with DRS compared with PTA, with PTA males having the highest incidence and DRS females the lowest (Figure 1). Treatment benefit with DRS appeared similar across sexes. Among females, 2-year event rates were 27.7% with DRS versus 51.6% with PTA (hazard ratio [HR], 0.48; 95% CI, 0.23-1.03; P = .06). Males showed a similar pattern, with significantly lower risk for DRS (32.7% vs 56.2%; HR, 0.48; 95% CI, 0.29-0.79; P = .003).
Figure 1.
Cumulative event rates for the primary efficacy end point through 2 years by treatment arm and sex. The primary efficacy end point, defined as freedom from above-ankle amputation, total occlusion of the target vessel, clinically-driven target lesion revascularization, and binary restenosis of the target lesion, is displayed here as cumulative event rates. Higher cumulative event rates were observed in the PTA arm compared with the DRS arm in both females and males. DRS, drug-eluting resorbable scaffold; PTA, percutaneous transluminal angioplasty.
Primary safety end point
Safety event rates remained low in all groups. At 2 years, rates were 9.1% (DRS males), 6.4% (DRS females), 4.7% (PTA males), and 3.8% (PTA females) (Figure 2). Events in DRS males occurred earlier, while PTA groups showed minimal events until ∼450 days.
Figure 2.
Cumulative event rates for the primary safety end point through 2 years by treatment arm and sex. The primary safety end point was defined as freedom from major adverse limb events (MALE) through 2 years and perioperative death (POD) within 30 days and is displayed here as cumulative event rates. MALE was defined as above-ankle amputation of the target limb or major reintervention (new surgical bypass graft, interposition graft, thrombectomy, or thrombolysis related to the target lesion). Cumulative MALE + POD event rates were low overall and remained comparable between treatment arms for both females and males through 2 years. DRS, drug-eluting resorbable scaffold; PTA, percutaneous transluminal angioplasty.
Binary restenosis
PTA was associated with substantially higher target lesion binary restenosis (TLBR) across sexes (Central Illustration). At 2 years, females had TLBR rates of 24.3% with DRS versus 53.9% with PTA (HR, 0.45; 95% CI, 0.21-0.98; P = .04). Males showed a similar trend (30.5% vs 46.3%; HR, 0.59; 95% CI, 0.35-1.01; P = .05). KM curves separated early and remained distinct.
Central Illustration.
Sex-stratified outcomes of DRS versus PTA in LIFE-BTK. A 2:1 randomized comparison of DRS and PTA by sex. Females presented with smaller vessels and greater ischemia, while males had more comorbidities and longer lesions. Despite these differences, sex did not independently influence outcomes. DRS consistently reduced restenosis and reintervention compared with PTA in both sexes, while females showed higher restenosis but fewer clinically-driven target lesion revascularization events. These findings support DRS benefit across sexes and highlight the importance of sex-specific surveillance strategies. The “# at Risk” values represent the number of patients in each subgroup who are still being followed at each time point and who have not yet experienced the event of interest. ABI, ankle-brachial index; BTK, below-the-knee; DRS, drug-eluting resorbable scaffold; PTA, percutaneous transluminal angioplasty; RCT, randomized controlled trial; RVD, reference vessel diameter.
CD-TLR
CD-TLR rates were consistently lower with DRS (Central Illustration). PTA females showed a late rise in events between 1 and 2 years (3.8% to 13.1%), while PTA males had a steady increase to 21.3%, the highest rate. At 2 years, CD-TLR rates were 8.1% (DRS) versus 13.1% (PTA) in females (nonsignificant), and 10.4% versus 21.3% in males, with a significant benefit for DRS (HR, 0.42; 95% CI, 0.18-0.96; P = .03).
Above-ankle amputation
Amputation incidence remained low across all groups (Figure 3). DRS showed numerically higher rates than PTA, but overall event numbers were small.
Figure 3.
Cumulative event rates for above-ankle amputation through 2 years by treatment arm and sex. Cumulative above-ankle amputation event rates were low and comparable between the DRS and PTA arms for both females and males through 2 years. DRS, drug-eluting resorbable scaffold; PTA, percutaneous transluminal angioplasty.
Sex-based differences in restenosis, reintervention, and TLBR/CD-TLR ratio
Six-month outcomes
At 6 months, females had nearly double the TLBR rates of males in both arms (DRS: 12.5% vs 7.2%; PTA: 15.1% vs 8.8%) (Table 5). Despite higher restenosis, females had markedly lower CD-TLR (DRS: 2% vs 4.6%; PTA: 0% vs 10%), and the opposite pattern was observed in males—lower TLBR but higher CD-TLR.
Table 5.
Kaplan–Meier estimated cumulative incidence rate of TLBR and CD-TLR by treatment and sex through 2 years.
| Days post procedure | Days post procedure | ||||
|---|---|---|---|---|---|
| 0 | 30 | 180 | 365 | 730 | |
| Target lesion binary restenosis | |||||
| DRS female | 0.0 | 5.4 | 12.5 | 20.2 | 24.3 |
| DRS male | 0.0 | 1.8 | 7.2 | 17.7 | 30.5 |
| PTA female | 0.0 | 0.0 | 15.1 | 34.4 | 53.9 |
| PTA male | 0.0 | 1.6 | 8.8 | 40.7 | 42.7 |
| Clinically-driven target lesion revascularization | |||||
| DRS female | 0.0 | 0.0 | 2.0 | 5.9 | 8.1 |
| DRS male | 0.0 | 0.9 | 4.6 | 7. | 10.4 |
| PTA female | 0.0 | 0.0 | 0.0 | 3.8 | 13.1 |
| PTA male | 8.2 | 8.2 | 10.0 | 17.3 | 21.3 |
Values are %.
CD-TLR, clinically-driven target lesion revascularization; DRS, drug-eluting resorbable scaffold; PTA, percutaneous transluminal angioplasty; TLBR, target lesion binary restenosis.
One-year outcomes
At 1 year, the TLBR–CD-TLR disconnect was greatest in the PTA arm (Table 5). Only ∼11% of PTA females with TLBR underwent CD-TLR (34.4% TLBR and 3.8% CD-TLR), compared with ∼43% of PTA males (40.7% and 17.3%, respectively). In the DRS arm, sex differences persisted but narrowed: females had slightly higher TLBR than males (20.2% vs 17.7%) and lower CD-TLR (5.9% vs 7.5%), corresponding to conversion rates of ∼29% in females and ∼42% in males.
Two-year outcomes
By 2 years, conversion ratios further underscored the discordance (Table 5). In the DRS arm, only about one-third of restenosis cases led to CD-TLR in either sex. In the PTA arm, females had the highest TLBR (∼54%), but only ∼24% underwent CD-TLR, whereas males, with lower TLBR (∼43%), had approximately half undergoing CD-TLR.
Discussion
In this sex-stratified analysis of the LIFE-BTK trial, treatment with DRS consistently showed lower event rates for the primary efficacy end point, binary restenosis, and CD-TLR at 1 and 2 years compared with PTA in both females and males. Importantly, sex was not significantly associated with clinical outcomes, and no sex-by-treatment interaction was observed. These findings indicate that the advantages of scaffold-based vessel preservation extend beyond early technical success and persist over time irrespective of patient sex, supporting its applicability across a broad CLTI population (Central Illustration).
However, the analysis revealed meaningful sex-related differences in baseline and procedural characteristics that may influence clinical decision making. Females were older, had smaller RVD, and presented with lower ABI values, suggesting more severe ischemia despite less complex lesions. The higher proportion of Hispanic/Latina females in the DRS arm is also notable and may reflect previously described disparities in access to PAD and CLTI care, potentially contributing to later presentation and more advanced ischemia at enrollment.18,19 Males exhibited higher rates of tobacco use, cardiovascular comorbidities, and longer, more calcified lesions. In this context, however, higher ABI values observed in males should be interpreted with caution, as a greater burden of renal disease, diabetes, and tobacco exposure may promote medial artery calcification, resulting in noncompressible vessels and falsely normal or elevated ABI measurements that underestimate ischemic severity.20, 21, 22 These patterns mirror prior reports of sex-related disparities in PAD7,9,10,23 and underscore the importance of considering anatomic and clinical differences when planning revascularization.
Despite these anatomic challenges, females treated with DRS achieved excellent technical success, with 100% reaching final diameter stenosis <30%, and experienced the lowest cumulative event rates. This observation suggests that scaffold-based therapy may be particularly advantageous in small-caliber vessels, where temporary mechanical support and targeted drug delivery are critical for durable outcomes. In contrast, PTA-treated females exhibited a distinct temporal pattern of failure, with minimal CD-TLR during the first year, followed by a sharp increase between years 1 and 2. This delayed failure likely reflects late lumen loss rather than early technical failure and emphasizes the need for extended surveillance in females after PTA, even when early results appear favorable.
One of the most intriguing findings was the discordance between restenosis and reintervention rates, particularly in females. At 6 months, females exhibited nearly twice the rate of binary restenosis compared with males in both treatment arms, yet they had substantially lower CD-TLR rates. By 1 year, the sex-related gap began to narrow in the DRS arm, whereas the PTA arm continued to display a marked imbalance, with females undergoing reintervention far less often despite a higher restenosis burden. At 2 years, this pattern persisted: PTA-treated females had the highest restenosis burden, but only 1 in 4 underwent reintervention, whereas PTA-treated males with lower restenosis rates had nearly half requiring CD-TLR. Several factors may explain this paradox. Females may experience less severe symptoms or present differently, reducing the likelihood of reintervention. Operators may adopt a more conservative approach in females due to smaller vessel size or perceived procedural risk.24 More prevalent baseline wound presence in males may have influenced reintervention thresholds, as ongoing tissue loss and failure of wound progression commonly drive repeat revascularization decisions in CLTI.25,26 Finally, restenosis morphology may differ by sex, with diffuse, non–flow-limiting patterns in females versus focal restenosis, causing greater hemodynamic compromise in males.27,28 Taken together, these results reinforce that restenosis does not consistently translate into reintervention, with early sex-based differences and a treatment-dependent pattern that is most pronounced after PTA and less evident with DRS, highlighting that sex-specific biological and clinical factors may influence treatment decisions.
In this context, it is notable that the observed reduction in event rates for the primary efficacy end point in females was largely driven by differences in binary restenosis. Although restenosis provides important mechanistic insight into device performance, its clinical translation appears attenuated in females, as reflected by similar early CD-TLR rates across treatment arms despite substantial differences in restenosis. In contrast, males showed a closer alignment between reduction in restenosis and lower CD-TLR rates, suggesting a more direct relationship between anatomic and clinical outcomes. The subsequent rise in CD-TLR observed in PTA-treated females beyond 1 year likely reflects a delayed clinical manifestation of restenosis rather than equivalent early durability. These findings suggest that reliance on reintervention alone may underestimate treatment effects in females and support the role of closer clinical and imaging-based surveillance after BTK intervention.
These findings have important clinical implications. DRS should be considered the preferred modality for BTK lesions, particularly in patients with small-caliber vessels and advanced ischemia. Females treated with PTA may require prolonged follow-up beyond 12 months, and understanding sex-specific anatomic and biological factors can inform procedural planning and postprocedural management. Although the relative benefit of DRS appears consistent across sexes, the observed trends, especially the discordance between restenosis and reintervention and delayed failure in PTA-treated females, warrant further investigation into vascular biology, healing responses, and operator decision making. Future CLTI trials should prioritize balanced enrollment of female participants to ensure study populations reflect real-world demographics. Additionally, sponsors, institutional review boards/ethics committees, and industry partners should strive for gender-diverse steering committees and principal investigators to support more equitable, evidence-based protocol development.7
This analysis shares limitations with the parent trial, including underrepresentation of females and exclusion of highly complex lesions—such as severe calcification, very long or TransAtlantic InterSociety Consensus class D lesions, and lesions unlikely to be crossed—which reflect a randomized controlled trial population but may underrepresent the most advanced real-world BTK disease, thereby limiting generalizability. The sex-based findings are exploratory and hypothesis-generating rather than conclusive. Moreover, the number of patients remaining at risk by 2 years in the KM analyses was very small—particularly among females—limiting the robustness of long-term, sex-stratified estimates. Additionally, the dataset included only binary biological sex (female/male) and did not capture gender identity, gender-related social determinants, or diversity of sex development. As a result, the findings may not be generalizable to gender-diverse populations. Future research should incorporate sex-stratified end points and symptom-driven measures, investigate biological mechanisms underlying restenosis and healing responses, and explore whether the benefits of DRS persist in real-world populations with more complex anatomy.
In summary, DRS provided a durable benefit over PTA across sexes, with no evidence of differential treatment effect. However, the patterns observed in this analysis underscore the need for sex-specific considerations in surveillance and management and highlight opportunities for personalized therapy in patients undergoing infrapopliteal interventions.
Conclusions
In this sex-stratified analysis of the LIFE-BTK trial, treatment with a DRS was consistently associated with lower event rates for the primary efficacy end point, binary restenosis, and CD-TLR compared with PTA at 1 and 2 years in both females and males. Sex was not associated with clinical outcomes, and no sex-by-treatment interaction was observed, indicating consistent relative benefit of DRS across sexes. Despite anatomical differences, procedural and clinical outcomes were comparable or favorable, particularly with DRS. These findings support the role of scaffold-based therapy as an effective option for BTK revascularization and highlight the need for future studies to explore sex-specific biological and clinical factors, symptom-driven thresholds for reintervention, and long-term durability in more complex real-world populations.
CRediT authorship contribution statement
Danielle R. Bajakian: Conceptualization, Supervision, Writing – original draft, Writing – review & editing. Serdar Farhan: Writing – review & editing. David J. O’Connor: Writing – review & editing. Zola N’Dandu: Writing – review & editing. Katherine Kane: Writing – review & editing. Sahil A. Parikh: Conceptualization, Supervision, Writing – review & editing. Brian G. DeRubertis: Conceptualization, Writing – review & editing. Ramon L. Varcoe: Conceptualization, Writing – review & editing. Shawn Yu: Data curation, Formal analysis. Karine Ruster: Conceptualization, Methodology, Supervision, Writing – original draft, Writing – review & editing. Brad Martinsen: Conceptualization, Writing – original draft, Writing – review & editing. Jennifer Meinen: Writing – review & editing. Zsuzsanna Igyarto: Conceptualization, Writing – original draft, Writing – review & editing. Prakash Krishnan: Writing – review & editing.
Acknowledgments
The authors thank Shih-Wa Ying and Jin Wang for study support and data analysis assistance.
Peer review statement
Associate Editor Sahil A. Parikh had no involvement in the peer review of this article and have no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to Deputy Editor Suzanne J. Baron.
Declaration of competing interest
Danielle R. Bajakian is on the advisory board for Abbott Vascular and Boston Scientific. Serdar Farhan has no conflicts of interest to disclose. David J. O’Connor serves as a speaker and faculty for Shockwave Medical. He is a principal investigator for a study funded by Boston Scientific and has received a research grant from Abbott Medical. Zola N’Dandu is a consultant for Abbott Vascular, BD, Terumo, Endologix, and Boston Scientific. He is on the advisory board of Provio Medical, Inc. Katherine Kane has no conflicts of interest to disclose. Sahil A. Parikh is a consultant for Abiomed, Terumo, Penumbra, and Canon. He holds equity interests in Encompass Vascular, Adv NanoTherapies, and eFemoral. He is on the advisory board for Abbott, Medtronic, Boston Scientific, Cordis, and Philips and has received institutional research support from Abbott, Acotec, Concept Medical, Shockwave Medical, Boston Scientific, Reflow Medical, FastWave, Veryan Medical, Philips, Cagent Vascular, Medinol, and AVS. Brian G. DeRubertis is a consultant for Abbott Vascular, Boston Scientific, Bard Peripheral, Cagent Vascular, Concept Medical, and Medtronic. Ramon L. Varcoe is a consultant for Medtronic, Abbott Vascular, BD, Intervene, Surmodics, Philips, Nectero, Endospan, Boston Scientific, Vesteck, W.L. Gore, R3 Vascular, Cook Medical, and Concept Medical. He holds equity in Provision Medical, Inc. and Vesteck. Shawn Yu, Karine Ruster, Brad J. Martinsen, Jennifer Meinen, and Zsuzsanna Igyarto are employed by and own stock in Abbott Vascular. Prakash Krishnan is a consultant for Medtronic and Abbott.
Funding sources
The LIFE-BTK study was funded by Abbott Vascular.
Ethics statement and patient consent
The LIFE-BTK trial was conducted in accordance with the principles of the Declaration of Helsinki, Good Clinical Practice guidelines, and applicable regulatory requirements. The study protocol was approved by the institutional review board or ethics committee at each participating site. All patients provided written informed consent prior to enrollment.
Declaration of generative AI and AI-assisted technologies in the writing process
During the preparation of this work, the authors used Microsoft Copilot in order to improve readability and language. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.
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