Critical Limb Ischemia : Prognostic Factors and Endovascular Strategies

Critical limb ischemia (CLI) is the final stage of peripheral arterial disease (PAD). Endovascular infrapopliteal treatment of patients with CLI using percutaneous transluminal angioplasty (PTA) and bail-out bare metal stenting (BMS) is hampered by restenosis. The PADI (Percutaneous transluminal Angioplasty and Drug-eluting Stents (DES) for Infrapopliteal lesions in critical limb ischemia) trial was conducted to assess whether DES improve patency and clinical outcome of infrapopliteal lesions. Adults with CLI and infrapopliteal lesions were randomized to receive PTA±BMS or DES. Primary endpoint was 6-month primary binary patency of treated lesions. Severity of treatment failure was assessed with an ordinal score, ranging from vessel restenosis (>50%), through occlusion, to clinical failure (re-intervention, major amputation, CLI-related death). Seventy-four limbs (73 patients) were treated with DES and 66 limbs (64 patients) received PTA±BMS. Six-month patency rates were 48.0% for DES and 35.1% for PTA±BMS (P=0.096). The ordinal score showed more severe treatment failures for PTA±BMS versus DES (P=0.041). The observed major amputation rate remained lower in the DES group until 2 years post-treatment (P=0.066). Less minor amputations (below ankle level) occurred after DES until 6 months post-treatment (P=0.03).Also at long-term up to 5 years follow-up, treatment of infrapopliteal lesions in CLI patients with DES yielded more favourable clinical results than with PTA±BMS. The estimated 5-year major amputation rate was lower in the DES arm than in the PTA±BMS arm (19.3% vs. 34.0%, respectively, P=0.091). The 5-year amputation-free survival and event-free survival (survival free from re-intervention or major amputation) rates were significantly higher in the DES arm (DES: 31.8% versus PTA±BMS: 20.4%; P=0.043; and DES: 26.2% versus PTA±BMS: 15.3%; P=0.041, respectively).Diabetes mellitus (DM) was highly prevalent in the PADI trial and as well in the JUVENTAS (reJUVenating ENdothelial progenitor cells via Transcutaneous intra-Arterial Supplementation) trial, a randomized controlled trial conducted in equivalent CLI patients. The two trials were pooled on patient level. The 5-year major amputation rate was higher in patients with DM than in non-diabetics (34.1% versus 20.4%, P=0.015). Death rates were comparable. Model factors with significant hazard ratios (HRs) in the multivariate analysis were baseline Rutherford category (HR 1.95; 95% CI 1.24-3.06) and ankle-brachial index (ABI) >1.4 (HR 2.78; 95% CI 1.37-5.64). CLI patients with DM are thus at significantly higher risk of major amputation than CLI patients without DM. This increased risk is associated with a higher prevalence of baseline ABI>1.4 and more severe ischemia at initial presentation in patients with DM.The prognostic value of the ABI concerning major amputation and survival in CLI patients with proven arterial obstructive disease was assessed in more detail in the same cohort of patients. Patients with a high (>1.4)/immeasurable ABI showed a significantly higher 5-year major amputation and lower 5-year amputation-free survival rates than those with an intermediate (0.7-1.4) and low (<0.7) ABI. High/immeasurable ABI at baseline was associated with a significantly higher risk of major amputation or death (HR 2.95, P<0.001). Incorporating high/immeasurable ABI in the existing PREVENT III prediction model regarding outcome in CLI significantly improved its performance

Critical Limb Ischemia : Prognostic Factors and Endovascular Strategies

Critical limb ischemia (CLI) is the final stage of peripheral arterial disease (PAD). Endovascular infrapopliteal treatment of patients with CLI using percutaneous transluminal angioplasty (PTA) and bail-out bare metal stenting (BMS) is hampered by restenosis. The PADI (Percutaneous transluminal Angioplasty and Drug-eluting Stents (DES) for Infrapopliteal lesions in critical limb ischemia) trial was conducted to assess whether DES improve patency and clinical outcome of infrapopliteal lesions. Adults with CLI and infrapopliteal lesions were randomized to receive PTA±BMS or DES. Primary endpoint was 6-month primary binary patency of treated lesions. Severity of treatment failure was assessed with an ordinal score, ranging from vessel restenosis (>50%), through occlusion, to clinical failure (re-intervention, major amputation, CLI-related death). Seventy-four limbs (73 patients) were treated with DES and 66 limbs (64 patients) received PTA±BMS. Six-month patency rates were 48.0% for DES and 35.1% for PTA±BMS (P=0.096). The ordinal score showed more severe treatment failures for PTA±BMS versus DES (P=0.041). The observed major amputation rate remained lower in the DES group until 2 years post-treatment (P=0.066). Less minor amputations (below ankle level) occurred after DES until 6 months post-treatment (P=0.03).Also at long-term up to 5 years follow-up, treatment of infrapopliteal lesions in CLI patients with DES yielded more favourable clinical results than with PTA±BMS. The estimated 5-year major amputation rate was lower in the DES arm than in the PTA±BMS arm (19.3% vs. 34.0%, respectively, P=0.091). The 5-year amputation-free survival and event-free survival (survival free from re-intervention or major amputation) rates were significantly higher in the DES arm (DES: 31.8% versus PTA±BMS: 20.4%; P=0.043; and DES: 26.2% versus PTA±BMS: 15.3%; P=0.041, respectively).Diabetes mellitus (DM) was highly prevalent in the PADI trial and as well in the JUVENTAS (reJUVenating ENdothelial progenitor cells via Transcutaneous intra-Arterial Supplementation) trial, a randomized controlled trial conducted in equivalent CLI patients. The two trials were pooled on patient level. The 5-year major amputation rate was higher in patients with DM than in non-diabetics (34.1% versus 20.4%, P=0.015). Death rates were comparable. Model factors with significant hazard ratios (HRs) in the multivariate analysis were baseline Rutherford category (HR 1.95; 95% CI 1.24-3.06) and ankle-brachial index (ABI) >1.4 (HR 2.78; 95% CI 1.37-5.64). CLI patients with DM are thus at significantly higher risk of major amputation than CLI patients without DM. This increased risk is associated with a higher prevalence of baseline ABI>1.4 and more severe ischemia at initial presentation in patients with DM.The prognostic value of the ABI concerning major amputation and survival in CLI patients with proven arterial obstructive disease was assessed in more detail in the same cohort of patients. Patients with a high (>1.4)/immeasurable ABI showed a significantly higher 5-year major amputation and lower 5-year amputation-free survival rates than those with an intermediate (0.7-1.4) and low (<0.7) ABI. High/immeasurable ABI at baseline was associated with a significantly higher risk of major amputation or death (HR 2.95, P<0.001). Incorporating high/immeasurable ABI in the existing PREVENT III prediction model regarding outcome in CLI significantly improved its performance

Diabetes Mellitus Is Associated With Decreased Limb Survival in Patients With Critical Limb Ischemia : Pooled Data From Two Randomized Controlled Trials

OBJECTIVE: Although never assessed prospectively, diabetes mellitus (DM) is assumed to negatively affect the outcomes of critical limb ischemia (CLI). DM was highly prevalent in two recently conducted randomized controlled trials in CLI patients, the PADI (Percutaneous Transluminal Balloon Angioplasty [PTA] and Drug Eluting Stents for Infrapopliteal Lesions in Critical Limb Ischemia) and JUVENTAS (Rejuvenating Endothelial Progenitor Cells via Transcutaneous Intra-Arterial Supplementation) trials. To determine the implications of DM in a population of patients with infrapopliteal CLI, clinical outcomes were compared in patients with and without DM. RESEARCH DESIGN AND METHODS: Individual data from patients with CLI (Rutherford category ≥4) were pooled. Patients were considered to have DM when this diagnosis was reported in the hospital electronic medical records. Rates of major amputation (above ankle level) and major events (major amputation or death) were compared between CLI patients with and without DM. Hazard ratios (HRs) were calculated. RESULTS: Of a total of 281 patients, DM was present in 49.1%. The major amputation rate at 5 years of follow-up was higher in patients with DM than in patients without DM (34.1% vs. 20.4%, P = 0.015). The major event and death rate did not differ. The unadjusted HR of DM for the major amputation risk was 1.87 (95% CI 1.12-3.12). Model factors with significant HRs in the multivariate analysis were baseline Rutherford category (HR 1.95; 95% CI 1.24-3.06) and ankle-brachial index (ABI) >1.4 (HR 2.78; 95% CI 1.37-5.64). CONCLUSIONS: CLI patients with DM are at a significantly higher risk of major amputation than CLI patients without DM. This increased risk is associated with a higher prevalence of baseline ABI >1.4 and more severe ischemia at initial presentation in patients with DM

Validation of randomized controlled trial-derived models for the prediction of postintervention outcomes in chronic limb-threatening ischemia

Background: Chronic limb-threatening ischemia (CLTI) represents the most severe form of peripheral artery disease and has a large impact on quality of life, morbidity, and mortality. Interventions are aimed at improving tissue perfusion and averting amputation and secondary cardiovascular complications with an optimal risk-benefit ratio. Several prediction models regarding postprocedural outcomes in CLTI patients have been developed on the basis of randomized controlled trials to improve clinical decision-making. We aimed to determine model performance in predicting clinical outcomes in selected CLTI cohorts. Methods: This study validated the Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL), Finland National Vascular registry (FINNVASC), and Prevention of Infrainguinal Vein Graft Failure (PREVENT III) models in data sets from a peripheral artery disease registry study (Athero-Express) and two randomized controlled trials of CLTI in The Netherlands, Rejuvenating Endothelial Progenitor Cells via Transcutaneous Intra-arterial Supplementation (JUVENTAS) and Percutaneous Transluminal Angioplasty and Drug-eluting Stents for Infrapopliteal Lesions in Critical Limb Ischemia (PADI). Receiver operating characteristic (ROC) curve analysis was used to calculate their predictive capacity. The primary outcome was amputation-free survival (AFS); secondary outcomes were all-cause mortality and amputation at 12 months after intervention. Results: The BASIL and PREVENT III models showed predictive values regarding postintervention mortality in the JUVENTAS cohort with an area under the ROC curve (AUC) of 81% and 70%, respectively. Prediction of AFS was poor to fair (AUC, 0.60-0.71) for all models in each population, with the highest predictive value of 71% for the BASIL model in the JUVENTAS population. The FINNVASC model showed the highest predictive value regarding amputation risk in the PADI population with AUC of 78% at 12 months. Conclusions: In general, all models performed poor to fair in predicting mortality and amputation. Because the BASIL model performed best in predicting AFS, we propose use of the BASIL model to aid in the clinical decision-making process in CLTI. However, improvements in performance have to be made for any of these models to be of real additional value in clinical practice

Diabetes Mellitus Is Associated With Decreased Limb Survival in Patients With Critical Limb Ischemia : Pooled Data From Two Randomized Controlled Trials

OBJECTIVE: Although never assessed prospectively, diabetes mellitus (DM) is assumed to negatively affect the outcomes of critical limb ischemia (CLI). DM was highly prevalent in two recently conducted randomized controlled trials in CLI patients, the PADI (Percutaneous Transluminal Balloon Angioplasty [PTA] and Drug Eluting Stents for Infrapopliteal Lesions in Critical Limb Ischemia) and JUVENTAS (Rejuvenating Endothelial Progenitor Cells via Transcutaneous Intra-Arterial Supplementation) trials. To determine the implications of DM in a population of patients with infrapopliteal CLI, clinical outcomes were compared in patients with and without DM. RESEARCH DESIGN AND METHODS: Individual data from patients with CLI (Rutherford category ≥4) were pooled. Patients were considered to have DM when this diagnosis was reported in the hospital electronic medical records. Rates of major amputation (above ankle level) and major events (major amputation or death) were compared between CLI patients with and without DM. Hazard ratios (HRs) were calculated. RESULTS: Of a total of 281 patients, DM was present in 49.1%. The major amputation rate at 5 years of follow-up was higher in patients with DM than in patients without DM (34.1% vs. 20.4%, P = 0.015). The major event and death rate did not differ. The unadjusted HR of DM for the major amputation risk was 1.87 (95% CI 1.12-3.12). Model factors with significant HRs in the multivariate analysis were baseline Rutherford category (HR 1.95; 95% CI 1.24-3.06) and ankle-brachial index (ABI) >1.4 (HR 2.78; 95% CI 1.37-5.64). CONCLUSIONS: CLI patients with DM are at a significantly higher risk of major amputation than CLI patients without DM. This increased risk is associated with a higher prevalence of baseline ABI >1.4 and more severe ischemia at initial presentation in patients with DM

Validation of randomized controlled trial-derived models for the prediction of postintervention outcomes in chronic limb-threatening ischemia

Background: Chronic limb-threatening ischemia (CLTI) represents the most severe form of peripheral artery disease and has a large impact on quality of life, morbidity, and mortality. Interventions are aimed at improving tissue perfusion and averting amputation and secondary cardiovascular complications with an optimal risk-benefit ratio. Several prediction models regarding postprocedural outcomes in CLTI patients have been developed on the basis of randomized controlled trials to improve clinical decision-making. We aimed to determine model performance in predicting clinical outcomes in selected CLTI cohorts. Methods: This study validated the Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL), Finland National Vascular registry (FINNVASC), and Prevention of Infrainguinal Vein Graft Failure (PREVENT III) models in data sets from a peripheral artery disease registry study (Athero-Express) and two randomized controlled trials of CLTI in The Netherlands, Rejuvenating Endothelial Progenitor Cells via Transcutaneous Intra-arterial Supplementation (JUVENTAS) and Percutaneous Transluminal Angioplasty and Drug-eluting Stents for Infrapopliteal Lesions in Critical Limb Ischemia (PADI). Receiver operating characteristic (ROC) curve analysis was used to calculate their predictive capacity. The primary outcome was amputation-free survival (AFS); secondary outcomes were all-cause mortality and amputation at 12 months after intervention. Results: The BASIL and PREVENT III models showed predictive values regarding postintervention mortality in the JUVENTAS cohort with an area under the ROC curve (AUC) of 81% and 70%, respectively. Prediction of AFS was poor to fair (AUC, 0.60-0.71) for all models in each population, with the highest predictive value of 71% for the BASIL model in the JUVENTAS population. The FINNVASC model showed the highest predictive value regarding amputation risk in the PADI population with AUC of 78% at 12 months. Conclusions: In general, all models performed poor to fair in predicting mortality and amputation. Because the BASIL model performed best in predicting AFS, we propose use of the BASIL model to aid in the clinical decision-making process in CLTI. However, improvements in performance have to be made for any of these models to be of real additional value in clinical practice

High and immeasurable ankle-brachial index as predictor of poor amputation-free survival in critical limb ischemia

OBJECTIVE: The objective of this study was to assess the prognostic value of a high or immeasurable ankle-brachial index (ABI) at baseline for major amputation and amputation-free survival (AFS) in patients with critical limb ischemia (CLI). METHODS: Data from two recent trials in patients with CLI and proven infrapopliteal arterial obstructive disease were pooled. Patients were allocated to the low (1.4)/immeasurable ABI subgroup. Major amputation and AFS rates were compared. Hazard ratios for major amputation and death were calculated. The net reclassification improvement of incorporating high/immeasurable ABI in the Project of Ex-Vivo vein graft Engineering via Transfection III (PREVENT III) prediction model was derived. RESULTS: There were 146 patients (56.2%) who had a low ABI, 81 patients (31.2%) who had an intermediate ABI, and 33 patients (12.7%) who had a high/immeasurable ABI at baseline. Patients with high/immeasurable ABI showed higher 5-year major amputation (52.1%) and lower 5-year AFS (5.0%) rates than the intermediate (25.5% and 41.6%, respectively) and low ABI patients (23.5% and 46.9%, respectively; both P < .001). This same trend was observed in subgroup analysis of diabetics and nondiabetics. Adjusted hazard ratio of high/immeasurable ABI for major amputation/death risk was 2.93 (P < .001). Adding a high/immeasurable ABI as model factor to the PREVENT III model yielded a net reclassification index of 0.38 (P < .0001). CONCLUSIONS: A high/immeasurable ABI in patients with CLI and infrapopliteal arterial obstructive disease is an independent risk factor of major amputation and of poor AFS, in both diabetics and nondiabetics. Incorporating high/immeasurable ABI in the PREVENT III prediction model improves its performance

Long-Term Follow-up of the PADI Trial : Percutaneous Transluminal Angioplasty Versus Drug-Eluting Stents for Infrapopliteal Lesions in Critical Limb Ischemia

BACKGROUND: Clinical outcomes reported after treatment of infrapopliteal lesions with drug-eluting stents (DESs) have been more favorable compared with percutaneous transluminal angioplasty with a bailout bare metal stent (PTA-BMS) through midterm follow-up in patients with critical limb ischemia. In the present study, long-term results of treatment of infrapopliteal lesions with DESs are presented. METHODS AND RESULTS: Adults with critical limb ischemia (Rutherford category ≥4) and infrapopliteal lesions were randomized to receive PTA-BMS or DESs with paclitaxel. Long-term follow-up consisted of annual assessments up to 5 years after treatment or until a clinical end point was reached. Clinical end points were major amputation (above ankle level), infrapopliteal surgical or endovascular reintervention, and death. Preserved primary patency (≤50% restenosis) of treated lesions was an additional morphological end point, assessed by duplex sonography. In total, 74 limbs (73 patients) were treated with DESs and 66 limbs (64 patients) were treated with PTA-BMS. The estimated 5-year major amputation rate was lower in the DES arm (19.3% versus 34.0% for PTA-BMS; P=0.091). The 5-year rates of amputation- and event-free survival (survival free from major amputation or reintervention) were significantly higher in the DES arm compared with PTA-BMS (31.8% versus 20.4%, P=0.043; and 26.2% versus 15.3%, P=0.041, respectively). Survival rates were comparable. The limited available morphological results showed higher preserved patency rates after DESs than after PTA-BMS at 1, 3, and 4 years of follow-up. CONCLUSIONS: Both clinical and morphological long-term results after treatment of infrapopliteal lesions in patients with critical limb ischemia are improved with DES compared with PTA-BMS. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00471289

Percutaneous Transluminal Angioplasty and Drug-Eluting Stents for Infrapopliteal Lesions in Critical Limb Ischemia (PADI) Trial

BACKGROUND: Endovascular infrapopliteal treatment of patients with critical limb ischemia using percutaneous transluminal angioplasty (PTA) and bail-out bare metal stenting (BMS) is hampered by restenosis. In interventional cardiology, drug-eluting stents (DES) have shown better patency rates and are standard practice nowadays. An investigator-initiated, multicenter, randomized trial was conducted to assess whether DES also improve patency and clinical outcome of infrapopliteal lesions. METHODS AND RESULTS: Adults with critical limb ischemia (Rutherford category ≥4) and infrapopliteal lesions were randomized to receive PTA±BMS or DES with paclitaxel. Primary end point was 6-month primary binary patency of treated lesions, defined as ≤50% stenosis on computed tomographic angiography. Stenosis >50%, retreatment, major amputation, and critical limb ischemia-related death were regarded as treatment failure. Severity of failure was assessed with an ordinal score, ranging from vessel stenosis through occlusion to the clinical failures. Seventy-four limbs (73 patients) were treated with DES and 66 limbs (64 patients) received PTA±BMS. Six-month patency rates were 48.0% for DES and 35.1% for PTA±BMS (P=0.096) in the modified-intention-to-treat and 51.9% and 35.1% (P=0.037) in the per-protocol analysis. The ordinal score showed significantly worse treatment failure for PTA±BMS versus DES (P=0.041). The observed major amputation rate remained lower in the DES group until 2 years post-treatment, with a trend toward significance (P=0.066). Less minor amputations occurred after DES until 6 months post-treatment (P=0.03). CONCLUSIONS: In patients with critical limb ischemia caused by infrapopliteal lesions, DES provide better 6-month patency rates and less amputations after 6 and 12 months compared with PTA±BMS. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00471289

Percutaneous Transluminal Angioplasty and Drug-Eluting Stents for Infrapopliteal Lesions in Critical Limb Ischemia (PADI) Trial

BACKGROUND: Endovascular infrapopliteal treatment of patients with critical limb ischemia using percutaneous transluminal angioplasty (PTA) and bail-out bare metal stenting (BMS) is hampered by restenosis. In interventional cardiology, drug-eluting stents (DES) have shown better patency rates and are standard practice nowadays. An investigator-initiated, multicenter, randomized trial was conducted to assess whether DES also improve patency and clinical outcome of infrapopliteal lesions. METHODS AND RESULTS: Adults with critical limb ischemia (Rutherford category ≥4) and infrapopliteal lesions were randomized to receive PTA±BMS or DES with paclitaxel. Primary end point was 6-month primary binary patency of treated lesions, defined as ≤50% stenosis on computed tomographic angiography. Stenosis >50%, retreatment, major amputation, and critical limb ischemia-related death were regarded as treatment failure. Severity of failure was assessed with an ordinal score, ranging from vessel stenosis through occlusion to the clinical failures. Seventy-four limbs (73 patients) were treated with DES and 66 limbs (64 patients) received PTA±BMS. Six-month patency rates were 48.0% for DES and 35.1% for PTA±BMS (P=0.096) in the modified-intention-to-treat and 51.9% and 35.1% (P=0.037) in the per-protocol analysis. The ordinal score showed significantly worse treatment failure for PTA±BMS versus DES (P=0.041). The observed major amputation rate remained lower in the DES group until 2 years post-treatment, with a trend toward significance (P=0.066). Less minor amputations occurred after DES until 6 months post-treatment (P=0.03). CONCLUSIONS: In patients with critical limb ischemia caused by infrapopliteal lesions, DES provide better 6-month patency rates and less amputations after 6 and 12 months compared with PTA±BMS. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00471289