Cell Therapy for Critical Limb Ischemia

Angiology ◽  
2015 ◽  
Vol 67 (5) ◽  
pp. 444-455 ◽  
Author(s):  
Aaron Liew ◽  
Vish Bhattacharya ◽  
James Shaw ◽  
Gerard Stansby
Keyword(s):  
Cell Therapy ◽  
Critical Limb Ischemia ◽  
Ulcer Healing ◽  
Mononuclear Cells ◽  
Ankle Brachial Index ◽  
Limb Ischemia ◽  
Major Amputation ◽  
Cochrane Library ◽  
Mortality Data ◽  
All Cause Mortality

Early-phase trials showed the feasibility and potential efficacy of cell therapy in patients with critical limb ischemia (CLI). For systematic review, randomized controlled trials (RCTs) of cell therapy versus no cell therapy in CLI were searched from PubMed and the Cochrane library databases. Outcome measures included major amputation, complete ulcer healing, ankle–brachial index (ABI), and all-cause mortality. Data were pooled using 16 RCTs, involving 774 patients. Compared with no cell therapy, cell therapy significantly reduced major amputation (odds ratio [OR]: 0.54; 95% CI: 0.34-0.87: P = .01) and improved ulcer healing (OR: 2.90; 95% confidence interval [CI]: 1.44-5.82; P < .01) and ABI (OR: 5.91; 95% CI: 1.85-18.86: P < .01). Peripheral blood-derived mononuclear cells (PB-MNCs; OR: 0.29; 95% CI: 0.12-0.72; P < .01) and bone marrow concentrate (OR: 0.44; 95% CI: 0.21-0.93; P = .03) significantly lowered the risk of major amputation. The PB-MNCs also significantly increased ulcer healing (OR: 5.77; 95% CI: 1.77-18.87; P < .01). All-cause mortality was similar in both groups (OR: 0.78; 95% CI: 0.44-1.40; P = .41). However, all estimates were nonsignificant following reanalysis using placebo-controlled RCTs only. Cell therapy remains a potential therapeutic option in CLI, but further larger placebo-controlled RCTs are needed.

scholarly journals Therapeutic efficacy of CD34+ cell-involved mononuclear cell therapy for no-option critical limb ischemia: A meta-analysis of randomized controlled clinical trials

2018 ◽  
Vol 23 (3) ◽  
pp. 219-231 ◽  
Author(s):  
Tianyue Pan ◽  
Zheng Wei ◽  
Yuan Fang ◽  
Zhihui Dong ◽  
Weiguo Fu
Keyword(s):  
Clinical Trials ◽  
Cell Therapy ◽  
Mononuclear Cell ◽  
Critical Limb Ischemia ◽  
Ulcer Healing ◽  
Meta Analysis ◽  
Limb Ischemia ◽  
Major Amputation ◽  
Therapeutic Benefit ◽  
Randomized Controlled

Early-phase clinical trials in patients with critical limb ischemia (CLI) have shown positive results of mononuclear cell therapy. The current meta-analysis investigated whether cluster of differentiation (CD) 34+ mononuclear cell therapy (CD34+MCT) is effective for no-option CLI. Ten randomized controlled clinical studies of CD34+MCT for no-option CLI with 479 patients were identified and analyzed for pooled results. Compared to control groups, the CD34+MCT was associated with lower total amputation (odds ratio (OR): 0.45, p=0.01; 95% confidence interval (CI): 0.24–0.85) and a higher complete ulcer healing rate (OR: 2.80, p=0.008; 95% CI: 1.31–6.02), but showed no advantage in major amputation (OR: 0.58, p=0.11; 95% CI: 0.29–1.14) and all-cause mortality (OR: 0.82, p=0.62; 95% CI: 0.36–1.83) . Studies with a high CD34+ cell dosage showed significant results in major amputation (OR: 0.38, p=0.002; 95% CI: 0.21–0.70), total amputation (OR: 0.31, p=0.0002; 95% CI: 0.17–0.57) and complete ulcer healing (OR: 7.58, p=0.0005; 95% CI: 2.40–23.88), which were not observed in the low-dose studies. However, inclusion of placebo-controlled studies showed no improvement of the CD34+MCT in total amputation (OR: 0.67, p=0.42; 95% CI: 0.25–1.79), major amputation (OR: 1.31, p=0.43; 95% CI: 0.67–2.54) or complete ulcer healing (OR: 1.52, p=0.27; 95% CI: 0.72–3.21), which were extremely significant in non-placebo-controlled studies ( p<0.001). In conclusion, the significant results of CD34+MCT might not support its therapeutic benefit due to high placebo-effect risk and considerable heterogeneity caused by distinct cell doses. More sizable double-blinded, randomized, placebo-controlled trials with higher CD34+ cell dosage are needed in the future.

Abstract P380: The Cardiovascular Fate in Patients with Amputation or Revascularization for Critical Limb Ischemia

Circulation ◽  
2014 ◽  
Vol 129 (suppl_1) ◽  
Author(s):  
Paola De Rango ◽  
Massimo Lenti ◽  
Enrico Cieri ◽  
Alessandro Marucchini ◽  
Luca Farchioni ◽  
...  
Keyword(s):  
Cardiovascular Mortality ◽  
Critical Limb Ischemia ◽  
Strong Predictor ◽  
Limb Ischemia ◽  
Major Amputation ◽  
Mortality And Morbidity ◽  
Primary Amputation ◽  
All Cause Mortality ◽  
And Gender ◽  
Cox Analysis

Background: Critical limb ischemia (CLI) continues to be a significantly morbid disease for the aging population with high likelihood of cardiovascular mortality and morbidity. Objective: To analyze incidence and timing of all cause and cardiovascular mortality (CM) in patients who survived after intervention for CLI. Methods: Patients consecutively discharged with diagnosis of CLI during the period 2006-2008 were re-evaluated for cardiovascular morbidity after 2 years. Patients receiving revascularization either open or endovascular and those with primary major amputation were compared with Kaplan-Meier analyses. The effect of treatment on outcome was analyzed with Cox analysis. Results: There were 257 patients (171 men, aged 74.12y), 39 treated by primary major amputation and 218 by revascularization. During a mean follow-up of 37months, 81 patients died for all cause mortality and 35 for CM. Mean survival time was 57.4months. More than half deaths (n=44) occurred by 15 months with 21 patients dying in the first 6 months and 33 within the first 12 months. Thirty-five myocardial infarctions and 15 strokes occurred. Cumulative survival rate at 60 months was 54% for all cause mortality and 79% for CM. There was significantly worse survival in patients with primary amputation when compared to those receiving revascularization: rates for all cause mortality were 45% vs. 75% (p=0.001) and rates for CM were 68% vs. 90% (p<0.0001), in primary amputation and revascularization group respectively at 42 months. Unadjusted odd ratios for all cause and cardiovascular mortality in patients with primary amputation vs. revascularization were 3.07 (95%CI 1.5-6.1, p=0.002) and 5.25 (95%CI 2.3-11.6, p<0.0001), respectively. After adjusting for age and gender, primary amputation persisted as independent predictor of all cause (HR 2.76, p<0.0001) and cardiovascular mortality (HR 5.11; p<0.0001). Conclusion: Mortality and CM after 2 years in patients surviving from CLI procedures are high. Primary amputation is a strong predictor of poor prognosis in the mid-long term for patients with CLI. Most deaths occur in the first 15 months after treatment. This data may question the benefits of revascularization.

Real-Time Quantitative Measurements of Foot Perfusion in Patients With Critical Limb Ischemia

2019 ◽  
Vol 53 (4) ◽  
pp. 310-315 ◽  
Author(s):  
O. Mironov ◽  
R. Zener ◽  
N. Eisenberg ◽  
K.T. Tan ◽  
Graham Roche-Nagle
Keyword(s):  
Wound Healing ◽  
Real Time ◽  
Critical Limb Ischemia ◽  
Ankle Brachial Index ◽  
Microvascular Disease ◽  
Limb Ischemia ◽  
Major Amputation ◽  
Rest Pain ◽  
Quantitative Measurements ◽  
Patients Experience

Introduction: Current methods of evaluating adequacy of endovascular procedures are imperfect and do not always predict which patients will do well. The purpose of this study was to evaluate the role of real-time quantitative measurements of perfusion among patients with critical limb ischemia. Materials and Methods: Thirty-four patients with critical limb ischemia undergoing endovascular treatment were recruited. Perfusion Images of the foot were obtained pre and post successful angioplasty using an SPY Elite System (Novadaq Technologies, Ontario, Canada). Patients were followed for 6 months. Subsequently a logistic regression was performed to determine whether intraprocedural perfusion parameters predicted the odds of wound healing. Results: Twenty-nine patients had successful angioplasty. Median age was 69.5% ± 8.3; 75% were men and 64% were diabetic. Rutherford stages were (4%-39%, 5%-57%, 6%-4%), and the average target limb ankle–brachial index (ABI) was 0.58 (SD 2.24). There was no significant correlation between the ABI and perfusion parameters. Inflow perfusion rate correlated significantly with Rutherford stage (Spearman rho 0.398, P = .036). After successful angioplasty 39% had a decrease in inflow rate and 57% had a decreased total inflow. In all, 25 patients completed 6 months of follow-up. Resolution of rest pain and/or healing of the ischemic wound occurred in 10 (40%) patients at 1 month, 4 (16%) at 3 months, and 2 (8%) at 6 months. One patient underwent a major amputation at 2 months. Eight (32%) patients never healed or had persistent rest pain. None of the real-time perfusion variables were significant predictors of wound healing. Conclusion: Many patients experience a paradoxical decrease in perfusion following successful angioplasty suggesting perfusion may not correlate with angiographic outcome, possibly due to microemboli, microvascular disease, or vasospasm. Real-time perfusion imaging following intra-arterial infusion of indocyanine green does not predict the odds of wound healing.

scholarly journals Relationship between cell number and clinical outcomes of autologous bone-marrow mononuclear cell implantation in critical limb ischemia

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Farina Mohamad Yusoff ◽  
Masato Kajikawa ◽  
Yuji Takaeko ◽  
Shinji Kishimoto ◽  
Haruki Hashimoto ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Therapy ◽  
Clinical Outcomes ◽  
Critical Limb Ischemia ◽  
Autologous Bone Marrow ◽  
Limb Ischemia ◽  
Major Amputation ◽  
Significant Difference ◽  
Autologous Bone ◽  
Death Group

AbstractCell therapy using intramuscular injections of autologous bone-marrow mononuclear cells (BM-MNCs) improves clinical symptoms and can prevent limb amputation in atherosclerotic peripheral arterial disease (PAD) patients with critical limb ischemia (CLI). The purpose of this study was to evaluate the effects of the number of implanted BM-MNCs on clinical outcomes in atherosclerotic PAD patients with CLI who underwent cell therapy. This study was a retrospective observational study with median follow-up period of 13.5 years (range, 6.8–15.5 years) from BM-MNC implantation procedure. The mean number of implanted cells was 1.2 ± 0.7 × 109 per limb. There was no significant difference in number of BM-MNCs implanted between the no major amputation group and major amputation group (1.1 ± 0.7 × 109 vs. 1.5 ± 0.8 × 109 per limb, P = 0.138). There was also no significant difference in number of BM-MNCs implanted between the no death group and death group (1.5 ± 0.9 × 109 vs. 1.8 ± 0.8 × 109 per patient, P = 0.404). Differences in the number of BM-MNCs (mean number, 1.2 ± 0.7 × 109 per limb) for cell therapy did not alter the major amputation-free survival rate or mortality rate in atherosclerotic PAD patients with CLI. A large number of BM-MNCs will not improve limb salvage outcome or mortality.

Abstract 510: Effect of Repetitive Intra-Arterial Infusion of Bone Marrow Mononuclear Cells in Patients With No-Option Limb Ischemia: The Randomized, Double-Blind, Placebo-Controlled JUVENTAS Trial

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Martin Teraa ◽  
Ralf W Sprengers ◽  
Roger E Schutgens ◽  
Ineke C Slaper-Cortenbach ◽  
Yolanda van der Graaf ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Relative Risk ◽  
Confidence Interval ◽  
Mononuclear Cells ◽  
Limb Ischemia ◽  
Major Amputation ◽  
Arterial Infusion ◽  
Double Blind ◽  
All Cause Mortality

Background: Patients with severe limb ischemia may not be eligible for conventional therapeutic interventions. Pioneering clinical trials suggest that bone marrow-derived cell therapy enhances neovascularization, improves tissue perfusion, and prevents amputation. The objective of this trial was to determine whether repetitive intra-arterial infusion of bone marrow mononuclear cells (BMMNCs) in patients with severe, nonrevascularizable limb ischemia can prevent major amputation. Methods and Results: The Rejuvenating Endothelial Progenitor Cells via Transcutaneous Intra-arterial Supplementation (JUVENTAS) trial is a randomized, double-blind, placebo-controlled clinical trial in 160 patients with severe, nonrevascularizable limb ischemia. Patients were randomly assigned to repetitive (3 times; 3-week interval) intraarterial infusion of BMMNC or placebo. No significant differences were observed for the primary outcome, ie, major amputation at 6 months, with major amputation rates of 19% in the BMMNC versus 13% in the placebo group (relative risk, 1.46; 95% confidence interval, 0.62-3.42). The safety outcome (all-cause mortality, occurrence of malignancy, or hospitalization due to infection) was not significantly different between the groups (relative risk, 1.46; 95% confidence interval, 0.63-3.38), neither was all-cause mortality at 6 months with 5% versus 6% (relative risk, 0.78; 95% confidence interval, 0.22-2.80). Secondary outcomes quality of life, rest pain, ankle-brachial index, and transcutaneous oxygen pressure improved during follow-up, but there were no significant differences between the groups. Conclusions: Repetitive intra-arterial infusion of autologous BMMNCs into the common femoral artery did not reduce major amputation rates in patients with severe, nonrevascularizable limb ischemia in comparison with placebo. The general improvement in secondary outcomes during follow-up in both the BMMNC and the placebo group, as well, underlines the essential role for placebo-controlled design of future trials. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00371371.

Intermittent intravenous urokinase for critical limb ischemia in diabetic foot ulceration

2008 ◽  
Vol 100 (09) ◽  
pp. 475-482 ◽  
Author(s):  
Matthias Weck ◽  
Hannes Rietzsch ◽  
Holger Lawall ◽  
Uwe Pichlmeier ◽  
Peter Bramlage ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase Ii ◽  
Critical Limb Ischemia ◽  
Ulcer Healing ◽  
Diabetic Foot ◽  
Controlled Trial ◽  
Limb Ischemia ◽  
Major Amputation ◽  
Diabetic Patients ◽  
Foot Ulceration

SummaryPatients with diabetic foot ulceration and critical limb ischemia have a high risk of major amputation, especially if limbs can not be revascularized. Urokinase is effective in improving microcirculation in critical limb ischemia and might improve outcomes. There are no data on the efficacy and safety of urokinase treatment (survival free of major amputation, ulcer healing and the rate of minor and major bleeding). Therefore, we aimed to investigate the effect of urokinase treatment in a phase II clinical trial. We performed an open, prospective, non-controlled, multi-center phase II cohort study in 77 type-2 diabetic patients with critical limb ischemia and diabetic foot ulceration. Patients had no surgical or endovascular treatment option based on interdisciplinary consensus. Urokinase (1 Mio IU if plasma fibrinogen ≥2.5 g/l, 0.5 Mio IU if fibrinogen < 2.5 g/l) was administered for 21 days as an intravenous infusion over 30 minutes. Each patient was followed up for 12 months. Treatment for a median of 21 days resulted in 33% of patients being alive, having no major amputation and completely healed ulcers after 12 months. Total survival rate was 84.6%,amputation-free survival 69.2% and rate of major amputation 21.1%.Eighty-two percent of patients experienced at least once a complete ulcer healing within the course of study. Three serious adverse events were urokinase-related. Urokinase treatment in diabetic patients with critical limb ischemia appears to be effective, feasible and safe. Although this calls for a larger, randomized and controlled trial, the results are highly relevant for clinical practice to prevent these patients from receiving major amputation due to diabetic foot syndrome.Clinical Trial Registration No.: NCT00537498

Falsely high ankle-brachial index predicts major amputation in critical limb ischemia

2006 ◽  
Vol 11 (2) ◽  
pp. 69-74 ◽  
Author(s):  
Antonio Silvestro ◽  
Nicolas Diehm ◽  
Hannu Savolainen ◽  
Do-Dai Do ◽  
Jolanda Vögele ◽  
...  
Keyword(s):  
Critical Limb Ischemia ◽  
Ankle Brachial Index ◽  
Limb Ischemia ◽  
Major Amputation

Abstract 16656: Drug Eluting Balloon Versus Percutaneous Transluminal Angioplasty Below the Knee Intervention for Critical Limb Ischemia: A Meta-analysis of Randomized Controlled Trials

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Muhammad Khalid ◽  
Mahmoud El Iskandarani ◽  
Vijay Ramu ◽  
Michael Donovan ◽  
Terry Forrest ◽  
...  
Keyword(s):  
Critical Limb Ischemia ◽  
Meta Analysis ◽  
Limb Ischemia ◽  
Target Lesion ◽  
Major Amputation ◽  
Transluminal Angioplasty ◽  
Below The Knee ◽  
All Cause Mortality ◽  
Drug Eluting ◽  
Drug Eluting Balloon

Introduction: Studies have shown decrease rates of restenosis and target lesion revascularization (TLR) with drug eluting balloon (DEB) in diabetic patients with critical limb ischemia (CLI). Hypothesis: The aim of this meta-analysis to compare the efficacy of DEB versus Percutaneous transluminal angioplasty (PTA) below the knee peripheral intervention. Methods: Electronic databases including MEDLINE, ClinicalTrials.gov and the Cochrane Library were searched for all randomized controlled trials (RCTs) published until April 2020 comparing outcomes of DEB vs PTA in patients with CLI below the knee. End points were major amputation, major adverse events (MAEs), all-cause mortality, target lesion revascularization (TLR), myocardial infarction, and cerebrovascular accidents (CVA). The risk ratio (RR) with 95% confidence interval (CI) were computed and p <0.05 was considered as a level of significance. Results: A total of 4 RCTs (n=655) were included in the final analysis. There were no differences of major amputation (RR: 1.30; CI: 0.68-2.46; p=0.43), MAEs (RR: 0.86; CI: 0.60-1.23; p=0.41), all-cause mortality (RR: 0.91; CI: 0.69-1.19; p=0.48), TLR (RR: 0.65; CI: 0.30-1.44; p=0.29), MI (RR: 1.71; CI: 0.57-5.14; p=0.34) and CVA (RR: 0.66; CI: 0.19-2.26; p=0.50) between the 2 groups [Figure 1]. Conclusions: There were no significant differences of major amputation and TLR for DEB versus PTA . Major adverse cardiac, cerebrovascular events and all-cause mortality were not statistically different for drug coated balloon versus PTA in the management of below knee critical limb ischemia. Further studies needed to confirm these findings.

Abstract 25: Critical Limb Ischemia Progression is Associated with an Inflammatory Profile

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Hendrik Gremmels ◽  
Martin Teraa ◽  
Joost O Fledderus ◽  
Olivier G de Jong ◽  
Yolanda van der Graaf ◽  
...  
Keyword(s):  
Disease Progression ◽  
Critical Limb Ischemia ◽  
Proportional Hazards ◽  
Independent Predictor ◽  
Controlled Trial ◽  
Ankle Brachial Index ◽  
Limb Ischemia ◽  
Major Amputation ◽  
Cox Proportional Hazards ◽  
Free Survival

Background: Patients with Critical Limb Ischemia (CLI) have a high risk of amputations and mortality. We hypothesize that inflammation is involved in atherosclerotic disease progression. In this study we investigate whether levels of plasma cytokines are associated with disease progression in CLI. Methods: Data were collected from a randomized controlled trial cohort investigating cell therapy for CLI (the JUVENTAS study) from 2006 to 2012. The primary outcome measures were major amputation and mortality at 6 months; secondary outcomes included Ankle/Brachial Index (ABI) and Transcutaneous O2 Pressure. Plasma was collected at inclusion in the study and a panel of cytokines consisting of GROa, HGF, LIF, SCF, SCGFb, SDF1a, TRAIL, IL-6, IL-8, FGFb, GCSF, GMCSF, IP10, MCP1, PDGFbb, RANTES, TNFa and VEGF was measured and evaluated for predictive power. Results: Data on 108 patients was collected with a follow-up of 6 months. Patients who underwent a major outcome had significantly higher levels of IL-6, IL-8 and GROa (p=0.0004, 0.006 and 0.009 resp.). Univariate Kaplan-Meier analysis showed that amputation-free survival was 94.4% in the lowest tertile, 74% in the middle tertile and 64% in the highest tertile of plasma IL-6 levels (p=0.009, Fig A). Adjustment for potential confounders in multivariate Cox proportional hazards models showed that IL-6 remained independent predictor of major outcome. The ROC of a model using Il-6 as single predictor for major outcomes is 0.73 (Fig. B) Conclusion: Plasma levels of inflammatory cytokines, in particular IL-6 are associated with disease progression in CLI and can serve as an independent predictor of amputation-free survival.

Sign in / Sign up

Export Citation Format

Share Document