Abstract
Background
Although several predictors affect long-term mortality in patients with lower extremity artery disease, long-term association of predictors on mortality over time remain unclear.
Objectives
The aim of this study was to explore the long-term and time-dependent association of baseline characteristics with mortality in patients with iliofemoral arterial disease.
Methods
This study is a multicenter retrospective analysis of 4,086 consecutive patients (mean age 72 ± 9 years, 74% men) who underwent endovascular therapy for symptomatic de novo iliofemoral arterial disease between January 2004 and December 2011 at 16 cardiovascular centers in Japan.
Results
During the median follow-up of 3.8 years (Q1-Q3: 1.4-7.4 years), 1,100 deaths, and 637 major adverse cardiovascular events (MACE) (defined as death, myocardial infarction, and stroke) were observed. Overall survival and MACE-free rates were estimated to be 56.1% and 50.6% at 10 years. Old age, chronic kidney disease stage, heart failure, the lack of renin-angiotensin-system inhibitor use, chronic limb threatening ischemia (CLTI), decreased ankle-brachial index, femoropopliteal lesion were significantly associated with an increased risk of mortality. while the prognostic impact of CLTI was significantly attenuated afterwards. Old age, chronic kidney disease stage, cerebrovascular disease, coronary artery disease, heart failure, warfarin use, the lack of statin use, and CLTI were significantly associated with an increased risk of MACE, while the prognostic impact of cerebrovascular disease and CLTI was significantly attenuated afterwards.
Conclusions
This study demonstrated long-term and time-dependent association of predictors on mortality and MACE following endovascular therapy. It highlights the need for continuous management of cardiovascular risk factors in this high-risk population.
Key Words: endovascular therapy, long-term, lower extremity artery disease, major adverse cardiovascular events, mortality
Central Illustration
Lower extremity artery disease (LEAD) is a common circulatory problem characterized by reduced blood flow to the limbs, often leading to significant morbidity and mortality.1, 2, 3 The iliofemoral segment is a frequent site of significant atherosclerotic obstruction, which can severely affect the quality of life because of claudication or chronic limb threatening ischemia (CLTI). Endovascular therapy (EVT) has emerged as a predominant treatment modality for symptomatic iliofemoral arterial disease, offering a minimally invasive alternative to conventional surgical approaches.4, 5, 6, 7, 8, 9, 10
Despite the high procedural success of iliofemoral endovascular interventions, long-term outcomes such as mortality and major adverse cardiovascular events (MACE) remain areas of substantial clinical interest and concern. These outcomes can be influenced by a myriad of baseline patient characteristics including demographic factors, comorbid conditions, and disease severity. Furthermore, it is also unclear whether the effect is constant over time. Additionally, mortality risks are significantly different between patients undergoing coronary and endovascular intervention.11 Understanding the association of these factors with long-term outcomes is crucial for optimizing patient selection, procedural approaches, and post-procedural care.1,12
The present study aims to explore the long-term association of these baseline characteristics over time with mortality and MACE in patients undergoing iliofemoral EVT for symptomatic LEAD.
Methods
Study population
We retrospectively analyzed a multicenter database of 4,086 consecutive patients who underwent EVT for symptomatic de novo iliofemoral artery disease between January 2004 and December 2011 at 16 cardiovascular centers in Japan. Baseline clinical characteristics and procedural data were collected from database by independent clinical researchers according to prespecified definitions. Clinical follow-up data were obtained by either a database or telephone contacts with the patients or their referring physicians. The study was conducted in accordance with the Declaration of Helsinki, and was approved by the Institutional Review Boards of the participating institutions. The requirement to obtain any informed consent was waived.
Outcome measures
The primary outcome measure of this study was all-cause mortality, and the secondary outcome measure was MACE.
Definitions
Myocardial infarction (MI) was defined by a significant elevation of serum biomarkers (troponin above the MI level or creatinine kinase levels twice normal) or new Q waves on the electrocardiogram. Coronary artery disease was defined as more than 50% stenosis in coronary vessel by angiography, history of coronary artery bypass graft surgery, or previous MI. Stroke was defined as cerebral stroke that persisted for at least 24 hours and indicated the occurrence of a neurological deficit. Chronic kidney disease (CKD) was regarded as present when creatinine clearance estimated by Cockcloft-Gould formula was <60 mL/min. Below-the-knee (BTK) artery disease was assessed by angiography before or after the procedure. BTK disease consisted of 2 or more occlusions of the following arteries: anterotibial artery, peroneal artery, or posterotibial artery. Poor BTK runoff was defined as 1 vessel or none of BTK runoff. MACE was defined as all-cause death, nonfatal MI, and nonfatal stroke.
Information on the following drug use at revascularization was collected: aspirin, thienopyridines, cilostazol, anticoagulants, statins, renin-angiotensin-system inhibitors, beta-blockers, and calcium-channel blockers.13, 14, 15, 16, 17 After the procedure, all patients were prescribed lifelong aspirin (100 mg/day) and prolonged (at least 1 month) clopidogrel 75 mg/d, ticlopidine 100 mg twice a day was recommended. However, data on drug use during the follow-up after revascularization was not collected in the present study.
Statistical analyses
Data are presented as mean ± SD for continuous variables or as percentages for discrete variables, if not otherwise mentioned. A P value <0.05 was considered statistically significant, and 95% CIs were reported where appropriate. The overall survival rate and the rate of free from MACE were estimated using the Kaplan-Meier method. We investigated the associations of baseline characteristics with the outcomes using the Cox regression model. The proportional hazards assumption regarding each variable of interest was checked by constructing the time-dependent covariate using time-transform functionality of coxph in the survival package in R, where we multiplied the variable of interest by the log-transformed analysis time. We calculated the fold changes in the HR by time as the exponential conversion of the time-dependent coefficient. When the null hypothesis that the regression coefficient of the time-dependent term time was zero was rejected, indicating that the proportional hazards assumption was violated, the time-dependent term was included in the subsequent multivariable Cox regression model. All baseline characteristics were included as the explanatory variables in the multivariable Cox regression model. Missing data were addressed using the multiple imputation by chained equations method. In the procedure, we generated 5 imputed data sets and combined the analytic results based on Rubin’s rule. All statistical analyses were performed using R version 3.6.0 (R Development Core Team).
Results
Baseline characteristics of the study population are presented in Table 1. Mean age was 72 ± 9 years, and the proportion of diabetes mellitus, CKD stage 5 (eGFR <15 mL/min/1.73 m2 or on dialysis), and heart failure (HF) was 54.6%, 21.3%, and 11.7%, respectively. CLTI accounted for 26.0%. At revascularization, aspirin was used in 3,521 patients (86.2%), thienopyridines were used in 2,045 patients (50.0%), cilostazol was used in 1,862 patients (45.6%), anticoagulants were used in 519 patients (12.7%), statins were used in 1,541 patients (37.7%), renin-angiotensin-system inhibitors were used in 2,130 patients (52.1%), beta-blockers were used in 1,010 patients (24.7%), and calcium-channel blockers were used in 1,827 patients (45.0%).
Table 1.
Baseline Characteristics of the Study Population (N = 4,086)
| Male | 3,026 (74.1) |
| Age, y | 72 ± 9 |
| Body mass index, kg/m2 | 22.3 ± 3.3 |
| Missing data | 306 (7.5) |
| Smoking history | 2,493 (61.0) |
| Diabetes mellitus | 2,232 (54.6) |
| Chronic kidney disease | |
| None, eGFR ≥60 mL/min/1.73 m2 | 1,386 (36.1) |
| Stage 3, eGFR 30-60 mL/min/1.73 m2 | 1,383 (36.0) |
| Stage 4, eGFR 15-30 mL/min/1.73 m2 | 255 (6.6) |
| Stage 5, eGFR <15 mL/min/1.73 m2 or on dialysis | 820 (21.3) |
| Missing data | 242 (5.9) |
| Cerebrovascular disease | 912 (22.3) |
| Coronary artery disease | 2,036 (49.8) |
| Heart failure | 479 (11.7) |
| Aspirin use | 3,521 (86.2) |
| Thienopyridine use | 2,045 (50.0) |
| Cilostazol use | 1,862 (45.6) |
| Anticoagulant use | 519 (12.7) |
| Statin use | 1,541 (37.7) |
| Renin-angiotensin-system inhibitor use | 2,130 (52.1) |
| Beta-blocker use | 1,010 (24.7) |
| Calcium-channel blocker use | 1,827 (45.0) |
| Missing data | 26 (0.6) |
| Chronic limb-threatening ischemia | 1,054 (26.0) |
| Missing data | 26 (0.6) |
| Ankle brachial index | 0.6 ± 0.2 |
| Missing data | 370 (9.1) |
| Poor below-the-knee runoff | 1,151 (29.1) |
| Missing data | 136 (3.3) |
| Femoropopliteal lesion | 2,792 (68.3) |
| Aortoiliac lesion | 2,157 (52.9) |
| Missing data | 9 (0.2) |
Values are n (%) or mean ± SD.
eGFR = estimated glomerular filtration rate.
During the median follow-up of 3.5 years (Q1-Q3: 1.4-7.2 years), 1,100 deaths and 637 MACEs were observed. The follow-up rate was 87.7% at 1 year, 68.5% at 3 years, 55.7% at 5 years, and 37.3% at 10 years. The overall survival rate was estimated to be 93.4% (95% CI: 92.6%-94.2%) at 1 year, 84.6% (95% CI: 83.4%-85.8%) at 3 years, 75.6% (95% CI: 74.0%-77.2%) at 5 years, and 56.1% (95% CI: 53.8%-58.5%) at 10 years (Figure 1). The MACE-free rates were estimated to be 91.5% (95% CI: 90.6%-92.4%) at 1 year, 81.3% (95% CI: 79.9%-82.6%) at 3 years, 71.6% (95% CI: 69.9%-73.2%) at 5 year, and 50.6% (95% CI: 48.3%-53.0%) at 10 years (Figure 1). Long-term survival and MACE-free rate on gender, CLTI, and ABI was shown in Supplemental Figure 1. There is no difference between gender. However, CLTI and ABI <0.6 were significantly lower survival and MACE-free.
Figure 1.
Overall Survival and MACE-Free Rates After Endovascular Therapy
Dotted lines indicate 95% CIs. MACE = major adverse cardiovascular events (including all-cause death, nonfatal myocardial infarction, and nonfatal stroke).
As shown in Table 2, sex, body mass index (BMI), statin use, renin-angiotensin-system inhibitor use, calcium-channel blocker use, CLTI, ankle brachial index (ABI), and poor BTK runoff demonstrated a significant time-dependent effect; the fold change in the HR per doubling of the follow-up time was 1.07 (95% CI: 1.00-1.14) (P = 0.040) for male sex, 1.08 (95% CI: 1.02-1.13) (P = 0.004) for BMI (per 5 kg/m2), 1.10 (95% CI: 1.03-1.18) (P = 0.004) for statin use, 1.12 (95% CI: 1.05-1.19) (P < 0.001) for renin-angiotensin-system inhibitor use, 1.10 (95% CI: 1.03-1.17) (P = 0.002) for calcium-channel blocker use, 0.77 (95% CI: 0.71-0.82) (P < 0.001) for CLTI, 1.02 (95% CI: 1.01-1.03) (P = 0.001) for ABI (per 0.1 unit), and 0.91 (95% CI: 0.85-0.96) (P = 0.001) for poor BTK runoff, indicating that the assumption of proportional hazards was violated regarding these variables. We therefore subsequently developed the multivariate model in which these variables accompanied their interaction term with time, whereas the other variables listed in Table 2 (age, smoking history, diabetes mellitus, chronic kidney disease, cerebrovascular disease, coronary artery disease, HF, aspirin use, thienopyridine use, cilostazol use, anticoagulant use, beta-blocker use, femoropopliteal lesion, and aortoiliac lesion) did not. Consequently, as summarized in Table 3, old age, CKD stage 3 to 5, HF, the lack of renin-angiotensin-system inhibitor use, CLTI, decreased ABI, and femoropopliteal lesion were significantly associated with an increased risk of all-cause mortality immediately after EVT (all P < 0.05), and the prognostic impact of CLTI, but not the others, was significantly attenuated afterwards; the fold change in the HR per doubling of the follow-up time was 0.81 (95% CI: 0.75-0.88) (P < 0.001).
Table 2.
Change in the Impact of Baseline Characteristics on the Risk of All-Cause Mortality During Follow-Up
| Male | 1.07 (1.00-1.14) (P = 0.040) |
| Age (per 10 y) | 1.02 (0.99-1.05) (P = 0.26) |
| Body mass index (per 5 kg/m2) | 1.08 (1.02-1.13) (P = 0.004) |
| Smoking history | 1.01 (0.95-1.07) (P = 0.74) |
| Diabetes mellitus | 1.02 (0.96-1.08) (P = 0.48) |
| Chronic kidney disease (vs none) | |
| Stage 3 | 1.06 (0.97-1.15) (P = 0.19) |
| Stage 4 | 0.94 (0.85-1.05) (P = 0.28) |
| Stage 5 | 0.98 (0.91-1.06) (P = 0.68) |
| Cerebrovascular disease | 0.95 (0.89-1.01) (P = 0.12) |
| Coronary artery disease | 1.02 (0.97-1.08) (P = 0.46) |
| Heart failure | 0.95 (0.88-1.01) (P = 0.11) |
| Aspirin use | 0.94 (0.87-1.03) (P = 0.20) |
| Thienopyridine use | 1.01 (0.95-1.07) (P = 0.70) |
| Cilostazol use | 0.99 (0.93-1.05) (P = 0.67) |
| Anticoagulant use | 1.02 (0.95-1.10) (P = 0.60) |
| Statin use | 1.10 (1.03-1.18) (P = 0.004) |
| Renin-angiotensin-system inhibitor use | 1.12 (1.05-1.19) (P < 0.001) |
| Beta-blocker use | 1.02 (0.96-1.09) (P = 0.51) |
| Calcium-channel blocker use | 1.10 (1.03-1.17) (P = 0.002) |
| Chronic limb-threatening ischemia | 0.77 (0.71-0.82) (P < 0.001) |
| Ankle brachial index (per 0.1 unit) | 1.02 (1.01-1.03) (P = 0.001) |
| Poor below-the-knee runoff | 0.91 (0.85-0.96) (P = 0.001) |
| Femoropopliteal lesion | 0.95 (0.88-1.02) (P = 0.14) |
| Aortoiliac lesion | 0.98 (0.92-1.04) (P = 0.44) |
Values are the fold change in the HR of each variable per doubling of the follow-up time (95% CIs) (P values).
Table 3.
Impact of Baseline Characteristics on Risk of All-Cause Mortality
| Male | 1.12 (0.60-2.09) (P = 0.73) |
| Interaction with time | 1.02 (0.95-1.08) (P = 0.61) |
| Age (per 10 y) | 1.52 (1.41-1.64) (P < 0.001) |
| Body mass index (per 5 kg/m2) | 0.64 (0.38-1.08) (P = 0.096) |
| Interaction with time | 1.02 (0.97-1.08) (P = 0.42) |
| Smoking history | 0.89 (0.78-1.03) (P = 0.11) |
| Diabetes mellitus | 0.99 (0.88-1.13) (P = 0.93) |
| Chronic kidney disease (vs none) | |
| Stage 3 | 1.30 (1.10-1.54) (P = 0.003) |
| Stage 4 | 2.61 (2.04-3.34) (P < 0.001) |
| Stage 5 | 3.47 (2.90-4.16) (P < 0.001) |
| Cerebrovascular disease | 1.07 (0.93-1.23) (P = 0.36) |
| Coronary artery disease | 1.07 (0.94-1.23) (P = 0.28) |
| Heart failure | 1.49 (1.26-1.76) (P < 0.001) |
| Aspirin use | 1.00 (0.84-1.18) (P = 0.97) |
| Thienopyridine use | 1.09 (0.95-1.24) (P = 0.22) |
| Cilostazol use | 1.00 (0.87-1.13) (P = 0.95) |
| Anticoagulant use | 1.15 (0.97-1.35) (P = 0.099) |
| Statin use | 0.77 (0.39-1.53) (P = 0.46) |
| Interaction with time | 1.01 (0.95-1.08) (P = 0.72) |
| Renin-angiotensin-system inhibitor use | 0.53 (0.29-0.97) (P = 0.041) |
| Interaction with time | 1.05 (0.99-1.12) (P = 0.12) |
| Beta-blocker use | 0.92 (0.80-1.06) (P = 0.26) |
| Calcium-channel blocker use | 0.64 (0.34-1.17) (P = 0.15) |
| Interaction with time | 1.05 (0.99-1.12) (P = 0.13) |
| Chronic limb-threatening ischemia | 14.48 (6.79-30.85) (P < 0.001) |
| Interaction with time | 0.81 (0.75-0.88) (P < 0.001) |
| Ankle brachial index (per 0.1 unit) | 0.88 (0.78-0.99) (P = 0.034) |
| Interaction with time | 1.01 (1.00-1.02) (P = 0.22) |
| Poor below-the-knee runoff | 0.96 (0.52-1.76) (P = 0.89) |
| Interaction with time | 1.01 (0.95-1.08) (P = 0.70) |
| Femoropopliteal lesion | 1.30 (1.08-1.56) (P = 0.005) |
| Aortoiliac lesion | 1.07 (0.92-1.25) (P = 0.37) |
Values are the adjusted HRs for mortality and their 95% CIs, derived from the multivariate model in which all the variables in the table were entered. Data on the interaction with time are presented as the fold change in the HR of each variable per doubling of the follow-up time.
The association of baseline characteristics with the MACE risk is demonstrated in Tables 4 and 5. Sex, BMI, cerebrovascular disease, HF, renin-angiotensin-system inhibitor use, CLTI, and ABI demonstrated a significant time-dependent effect; the fold change in the HR per doubling of the follow-up time was 1.08 (95% CI: 1.03-1.14) (P = 0.003) for male sex, 1.04 (95% CI: 1.00-1.08) (P = 0.044) for BMI (per 5 kg/m2), 0.92 (95% CI: 0.87-0.97) (P = 0.001) for cerebrovascular disease, 0.94 (95% CI: 0.89-1.00) (P = 0.039) for HF, 1.06 (95% CI: 1.01-1.11) (P = 0.015) for renin-angiotensin system inhibitor use, 0.85 (95% CI: 0.81-0.90) (P < 0.001) for CLTI, and 1.01 (95% CI: 1.00-1.02) (P = 0.006) for ABI (per 0.1 unit) (Table 4). The subsequent multivariable Cox regression model demonstrated that old age, CKD stage 3 to 5, cerebrovascular disease, coronary artery disease, HF, warfarin use, the lack of statin use, and CLTI were significantly associated with an increased risk of MACE immediately after EVT (all P < 0.05), while the prognostic impact of cerebrovascular disease and CLTI was significantly attenuated afterwards; the fold change in the HR per doubling of the follow-up time was 0.93 (95% CI: 0.88-0.98) (P = 0.005) and 0.91 (95% CI: 0.86-0.96) (P = 0.001), respectively (Table 5).
Table 4.
Change in the Impact of Baseline on the Risk of MACE During the Follow-Up Period
| Male | 1.08 (1.03-1.14) (P = 0.003) |
| Age (per 10 y) | 1.02 (0.99-1.04) (P = 0.25) |
| Body mass index (per 5 kg/m2) | 1.04 (1.00-1.08) (P = 0.044) |
| Smoking history | 1.02 (0.97-1.07) (P = 0.53) |
| Diabetes mellitus | 1.00 (0.95-1.04) (P = 0.86) |
| Chronic kidney disease (vs none) | |
| Stage 3 | 1.02 (0.95-1.09) (P = 0.59) |
| Stage 4 | 0.99 (0.91-1.09) (P = 0.90) |
| Stage 5 | 1.03 (0.96-1.09) (P = 0.43) |
| Cerebrovascular disease | 0.92 (0.87-0.97) (P = 0.001) |
| Coronary artery disease | 1.02 (0.97-1.07) (P = 0.40) |
| Heart failure | 0.94 (0.89-1.00) (P = 0.039) |
| Aspirin use | 0.96 (0.89-1.03) (P = 0.21) |
| Thienopyridine use | 1.00 (0.95-1.05) (P = 0.98) |
| Cilostazol use | 1.01 (0.96-1.06) (P = 0.76) |
| Anticoagulant use | 0.99 (0.93-1.05) (P = 0.62) |
| Statin use | 1.03 (0.98-1.09) (P = 0.19) |
| Renin-angiotensin-system inhibitor use | 1.06 (1.01-1.11) (P = 0.015) |
| Beta-blocker use | 1.01 (0.96-1.07) (P = 0.65) |
| Calcium-channel blocker use | 1.04 (0.99-1.09) (P = 0.11) |
| Chronic limb-threatening ischemia | 0.85 (0.81-0.90) (P < 0.001) |
| Ankle brachial index (per 0.1 unit) | 1.01 (1.00-1.02) (P = 0.006) |
| Poor below-the-knee runoff | 0.96 (0.91-1.01) (P = 0.082) |
| Femoropopliteal lesion | 0.98 (0.92-1.03) (P = 0.39) |
| Aortoiliac lesion | 0.97 (0.93-1.02) (P = 0.22) |
Values are the fold change in the HR of each variable per doubling of the follow-up time (95% CIs) (P values).
MACE = major adverse cardiovascular events (including all-cause death, nonfatal myocardial infarction and nonfatal stroke).
Table 5.
Impact of Baseline Characteristics on Risk of MACE
| Male | 0.79 (0.48-1.30) (P = 0.35) |
| Interaction with time | 1.05 (1.00-1.11) (P = 0.057) |
| Age (per 10 y) | 1.42 (1.32-1.52) (P < 0.001) |
| Body mass index (per 5 kg/m2) | 0.82 (0.55-1.23) (P = 0.34) |
| Interaction with time | 1.00 (0.96-1.04) (P = 0.89) |
| Smoking history | 0.92 (0.81-1.04) (P = 0.18) |
| Diabetes mellitus | 1.01 (0.90-1.13) (P = 0.91) |
| Chronic kidney disease (vs none) | |
| Stage 3 | 1.18 (1.01-1.38) (P = 0.035) |
| Stage 4 | 2.16 (1.71-2.73) (P < 0.001) |
| Stage 5 | 2.87 (2.43-3.38) (P < 0.001) |
| Cerebrovascular disease | 2.31 (1.43-3.73) (P = 0.001) |
| Interaction with time | 0.93 (0.88-0.98) (P = 0.005) |
| Coronary artery disease | 1.17 (1.04-1.33) (P = 0.010) |
| Heart failure | 2.15 (1.27-3.63) (P = 0.004) |
| Interaction with time | 0.96 (0.90-1.01) (P = 0.12) |
| Aspirin use | 0.96 (0.82-1.13) (P = 0.65) |
| Thienopyridine use | 1.09 (0.96-1.23) (P = 0.17) |
| Cilostazol use | 1.00 (0.88-1.12) (P = 0.94) |
| Anticoagulant use | 1.17 (1.00-1.36) (P = 0.048) |
| Statin use | 0.87 (0.77-0.98) (P = 0.027) |
| Renin-angiotensin-system inhibitor use | 0.69 (0.44-1.11) (P = 0.13) |
| Interaction with time | 1.03 (0.98-1.08) (P = 0.29) |
| Beta-blocker use | 0.95 (0.83-1.09) (P = 0.46) |
| Calcium-channel blocker use | 1.01 (0.90-1.13) (P = 0.92) |
| Chronic limb-threatening ischemia | 4.82 (2.79-8.32) (P < 0.001) |
| Interaction with time | 0.91 (0.86-0.96) (P = 0.001) |
| Ankle brachial index (per 0.1 unit) | 0.93 (0.85-1.01) (P = 0.089) |
| Interaction with time | 1.00 (0.99-1.01) (P = 0.57) |
| Poor below-the-knee runoff | 1.05 (0.91-1.20) (P = 0.53) |
| Femoropopliteal lesion | 1.18 (0.99-1.39) (P = 0.060) |
| Aortoiliac lesion | 1.04 (0.90-1.20) (P = 0.56) |
Values are the adjusted HRs for major adverse cardiovascular events (MACE) (including all-cause death, nonfatal myocardial infarction and nonfatal stroke) and their 95% CIs, derived from the multivariate model in which all the variables in the table were entered. Data on the interaction with time are presented as the fold change in the HR of each variable per doubling of the follow-up time.
Discussion
The findings of our study provide significant insights into the long-term outcomes of patients with symptomatic LEAD undergoing iliofemoral EVT. In particular, our analysis has delineated several baseline characteristics that are associated with increased risks of mortality and MACE over the follow-up period (Central Illustration).
Central Illustration.
Long-Term and Time-Dependent Association of Predictors on Mortality
This study is a multicenter retrospective study to evaluate the long-term mortality and time-dependent association of predictors on mortality in patients receiving endovascular therapy (EVT) for iliofemoral artery disease. The overall survival rate was 93.4% at 1 year, 75.6% at 5 years, and 56.1% at 10 years. The major adverse cardiovascular events (MACE)–free rate was 91.5% at 1 year, 71.6% at 5 years, and 50.6% at 10 years. Old age, chronic kidney disease (CKD) stage 3 to 5, heart failure, the lack of renin-angiotensin-system (RAS) inhibitor use, chronic limb-threatening ischemia (CLTI), decreased ankle-brachial index (ABI), and femoropopliteal lesion were significantly associated with an increased risk of mortality, while the prognostic impact of CLTI was significantly attenuated afterwards.
Mortality and MACE outcomes
Our study observed a decline in survival rates from 93.4% at 1 year to 56.1% at 10 years, highlighting a substantial long-term mortality risk in this population. Similarly, MACE-free rates decreased significantly over time. These findings are consistent with previous studies,1, 2, 3,18,19 which suggest that despite the initial procedural success, patients with LEAD remain at high risk for adverse cardiovascular outcomes, underscoring the need for ongoing risk management.
Associations of baseline character and outcomes
Several baseline characteristics were identified as predictors of poor outcomes. Age and the presence of CKD (stages 3-5), HF, and CLTI were strongly associated with increased mortality. Interestingly, the prognostic impact of CLTI on mortality attenuated over time, suggesting that its initial severity may overshadow other factors in the short term but becomes less predictive as patients survive the early post-procedural period.
The violation of the proportional hazards assumption for several variables (such as sex, body mass index, and use of specific medications) in crude models led us to incorporate interaction terms with time in our multivariate analysis. This adjustment revealed a nuanced picture of how the impact of various factors evolves over time, emphasizing the dynamic nature of risk in this patient population. Also, HF, which has been known to be a predictor of poor long-term prognosis, was also found to be a risk factor in LEAD patients after revascularization in this study.20
Pharmacological interventions
In particular, the lack of renin-angiotensin-system inhibitor and statin use emerged as significant predictors of increased risk. These findings align with current guidelines1, 2, 3,21 that advocate for aggressive medical management,22,23 including statins and renin-angiotensin-system inhibitor to mitigate cardiovascular risk in LEAD patients.
It has also been reported that active antihypertension is beneficial regardless of age or blood pressure level.24
Our data reinforces the importance of these medications in not only managing lipid levels and blood pressure but also in potentially improving long-term survival and reducing MACE in patients with LEAD undergoing revascularization.
Clinical implications and future research
The significant interaction effects and the attenuated impact of certain conditions over time suggest that LEAD management should focus not only on immediate postprocedural care but also on long-term strategies tailored to individual patient risk profiles. Future research should aim to optimize such strategies, potentially incorporating newer therapeutic agents and more refined risk stratification tools.
Moreover, our findings underscore the necessity for a multidisciplinary approach to LEAD management that integrates cardiology, nephrology, and vascular medicine to address the complex interplay of comorbid conditions influencing outcomes.
By delineating the predictive value of these characteristics, this research hopes to contribute to the personalized care of LEAD patients, enhancing both survival rates and quality of life postintervention.
Study limitations
There are several limitations that may have affected our clinical outcomes. First, this study was a retrospective, nonrandomized analysis, despite being from a large-scale, multicenter study. Second, our study included only Japanese patients, so the results should be confirmed for other ethnic groups. Finally, changes in medical practices over the study's long follow-up period may affect the generalizability of the results to current populations.
Conclusions
This study demonstrated the inter-relationships between baseline characteristics and long-term mortality and MACE in patients undergoing iliofemoral EVT for LEAD. It highlights the need for vigilant, ongoing management of cardiovascular risk factors in this high-risk population.
Funding Support and Author Disclosures
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Footnotes
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.
Appendix
For a supplemental figure, please see the online version of this paper.
Appendix
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