Abstract
Aims
Data about long‐term clinical outcomes of revascularization procedures, especially for autologous cell therapy (ACT), in diabetic patients with chronic limb‐threatening ischaemia (CLTI) are lacking. The aim of our study was to compare the mortality and amputation rates in patients with diabetic foot ulcers (DFU) and CLTI treated by ACT with patients treated by repeated percutaneous transluminal angioplasty (re‐PTA) and those treated conservatively.
Materials and Methods
One‐hundred and thirty patients with DFU and CLTI (defined as transcutaneous oxygen pressure—TcPO2 <30 mmHg after unsuccessful standard revascularization) treated in our foot clinic over 9 years were enrolled in the study. Forty‐five patients were treated by ACT, 43 patients underwent re‐PTA, and 42 patients were treated conservatively and formed the control group. Overall survival, amputation‐free survival (AFS) and major amputation rate were assessed over a 7‐year follow‐up period.
Results
Baseline demographic characteristics and comorbidities were similar between groups. However, patients in ACT and control groups had significantly worse baseline angiograms in accordance with Graziani and GLASS (infrapopliteal region) classifications than the re‐PTA group (both p < 0.001), but there were no differences in baseline values of TcPO2 between groups. AFS in the ACT and re‐PTA groups were significantly longer compared to control (both p < 0.001). The rate of major amputation was significantly lower in both active groups (both p < 0.001). The re‐PTA group showed significantly longer overall survival compared to the control group (p < 0.001), but there was no significant difference between ACT and control groups (p = 0.063) and ACT and re‐PTA groups (p = 0.081) in this parameter.
Conclusions
Our study showed significantly longer AFS and lower major amputation rates in patients treated by ACT and re‐PTA in contrast to patients treated conservatively. Overall survival was significantly longer only in the re‐PTA group. ACT was shown to be effective in long‐term limb salvage in people with no‐option CLTI.
Keywords: cellular research, clinical trial, diabetes complications, effectiveness
1. INTRODUCTION
The global prevalence of diabetes mellitus has been steadily increasing, currently affecting nearly half a billion people worldwide, with projections indicating a rise of more than 50% in the next 25 years. 1 Notably, individuals with type 2 diabetes (T2D) experience an average reduction in life expectancy of up to 10 years and face a diminished quality of life due to a heightened risk of cardiovascular disease. 2 Furthermore, cardiovascular complications significantly burden healthcare systems, accounting for 11% of total healthcare expenditure in European countries (estimated to cost the EU €282 billion annually). 3 Peripheral arterial disease (PAD) is often not diagnosed in people with diabetes, even though it is a very frequent complication of diabetic foot disease, and therefore, patients usually come in at later stages of limb ischaemia.
PAD as a macrovascular complication of diabetes significantly decreases the quality of life of people with diabetes and its most severe form, chronic limb‐threatening ischaemia (CLTI) increases cardiovascular mortality more than twice that compared to those with intermittent claudication. 4 Standard revascularization strategies for patients with CLTI are percutaneous transluminal angioplasty and vascular bypass. Both these treatment options were compared in two studies, BASIL‐2 and BEST‐CLI. 5 , 6 BASIL‐2 found that endovascular treatment was superior to vein bypass, with better amputation‐free survival (53% vs. 63% event rate, adjusted HR 1.35, p = 0.037). 5 On the other hand, BEST‐CLI showed that in patients with good quality single‐segment great saphenous vein (cohort 1), surgical bypass was superior to endovascular therapy, with a 32% reduction in Major Adverse Limb Event (MALE) or death (HR 0.68, p < 0.001). 6
Even though there have been some newer techniques to treat CLTI such as free bypass flap to resolve the issue with insufficient outflow vessels, 7 still up to 25% of patients with CLTI who are not eligible for standard revascularization; termed as no‐option CLTI (NO‐CLTI) especially those with infrapopliteal impairment which form the majority of patients with DM and NO‐CLTI. 8 The 1‐year mortality of NO‐CLTI people is up to 25% and major amputation of around 30%. 9
Autologous cell therapy (ACT) is a promising alternate option for people with diabetes and NO‐CLTI predominantly those with infrapopliteal location of arterial stenosis/obliterations. This therapy in accordance with most of the published studies improves ischaemia parameters (transcutaneous oxygen pressure—TcPO2 or ankle‐brachial index—ABI) and in many cases leads to limb salvage of those patients. 9 , 10 , 11 Although many randomized controlled trials have demonstrated the efficacy and safety of ACT in CLTI patients 12 , 13 , 14 some studies have shown the contrary. 15 Most recent reviews and meta‐analyses conclude that even though ACT does not always ‘save the limb’, it can form part of a comprehensive treatment to improve ischaemia and together with appropriate antibiotic treatment, offloading and diabetes control could improve the amputation‐free survival (AFS) in patients with NO‐CLTI. 10 , 16 , 17
The aim of the study was to compare the mortality and major amputation rates in people with diabetic foot ulcers (DFU) and CLTI treated by ACT with patients treated by repeated percutaneous transluminal angioplasty (re‐PTA) and those treated conservatively.
2. METHODS
2.1. Study schedule
One‐hundred and thirty patients with DFU and CLTI (defined as TcPO2 <30 mmHg after unsuccessful standard revascularization) treated in our foot clinic over 9 years were included in this non‐randomized retrospective single‐centre controlled trial.
2.2. Study groups
Forty‐five patients were treated by ACT, 43 patients underwent re‐PTA and 42 patients were treated conservatively and formed the control group (Table 1). All groups received standard treatment in the foot clinic as recommended by the International Working Group for the Diabetic Foot. 18 For infected ulcers, appropriate antibiotic therapy was administered, and in urgent cases, immediate hospital admission was arranged. Patients requiring pressure offloading were provided with therapeutic footwear or orthotics as recommended by the latest guidelines. All patients underwent detailed examinations for virological (hepatitis, HIV, syphilis) and genetic coagulation disorders (Leiden, prothrombin mutations, deficiency in protein C, S and antithrombin III). Oncology screening was performed, including mammographic and gynaecological examinations for women and urology examinations for men.
TABLE 1.
Baseline characteristics of the patients.
| ACT (n = 45) | Re‐PTA (n = 43) | Controls (n = 42) | p | |
|---|---|---|---|---|
| Age (years) | 64.4 ± 14 | 62.9 ± 10.9 | 67.5 ± 9 | 0.57 |
| Gender (% of men) | 80 | 74.4 | 71.4 | 0.64 |
| Type of diabetes (% of T2D) | 82.2 | 90.7 | 90.5 | 0.49 |
| Diabetes duration (years) | 24.2 ± 13.2 | 19.6 ± 8.5 | 20.9 ± 10.8 | 0.31 |
| Glycated haemoglobin (mmol/mol) | 59.6 ± 14.1 | 64.6 ± 18.6 | 62 ± 15.2 | 0.73 |
| Ischaemic heart disease (%) | 64.4 | 53.5 | 45.2 | 0.67 |
| Hypertension (%) | 91.1 | 81.4 | 92.9 | 0.71 |
| Dialysis (%) | 20 | 16.3 | 14.2 | 0.66 |
| Immunosuppressive therapy | 17.8 | 14 | 11.9 | 0.17 |
| Graziani classification | 5.0 ± 0.9 | 3.5 ± 1.1 | 5.1 ± 0.8 | <0.001 |
| GLASS infrapopliteal score | 3.2 ± 0.6 | 2.0 ± 0.9 | 3.1 ± 0.5 | <0.001 |
| Rutherford category | 4.96 ± 0.5 | 4.95 ± 0.21 | 4.93 ± 0.22 | 0.81 |
| Baseline TcPO2 values | 17.7 ± 10.4 | 21.1 ± 9.4 | 16.5 ± 9.8 | 0.44 |
The cell therapy product for ACT was manufactured in accordance with the Best Clinical Practice ACT procedure as described before. 19 Briefly, it included initially a regional (epidural) anaesthesia in the operating room, with the possibility of sedation depending on the patient's condition. Subsequently, in the prone position, bone marrow aspiration was performed using the standard Jamshidi technique (from one or both iliac crests). The total volume of 240 mL of collected bone marrow aspirate was mixed in a 400 mL bag with 30 mL of anticoagulant citrate dextrose. It was then filtered through an infusion set into 4 × 60 mL syringes. The entire volume was transferred to separation containers and processed using gradient density centrifugation over 14 min (5°C and 1500 rpm) using the Harvest SmartPrep2 (Harvest Technologies Corporation, Plymouth, MA, USA). Following this separation, plasma was aspirated from the containers, and a total of 40 mL of bone marrow concentrate was obtained. The main active substance in the cell suspension is bone marrow‐derived mononuclear cells (BMMNCs). A total of 40 mL of the cell suspension was then divided into 10 mL syringes in the operating room. After disinfecting the affected lower limb, the suspension was injected deeply into the muscles of the calf and foot along the tibial arteries and a peroneal artery, with 40–50 punctures delivering 1–2 mL per injection, and circularly around the site of the foot ulcer. Following the injection, the limb was gently washed with saline and bandaged. The patient was monitored in the ward for the next 5 days for any acute complications (all patients were examined with ultrasound of gluteus maximus for possible hematoma monitoring). The whole ACT procedure was done only once with no repeat applications.
Repeated PTA was performed by a standard technique at our vascular centre. All of the angioplasty procedures were performed from the groin using the ipsilateral approach and 4‐ and 5‐F access sheaths. The balloon catheters used for PTA had a diameter of 2–3.5 cm and were 2–10 cm long. All patients were administered intraarterial heparin 5000 IU at the start of the procedure; in the event of a complicated PTA procedure or an inadequate revascularization response, low‐molecular weight heparin was additionally administered at weight‐dependent doses for 2–3 days after the procedure.
Patients with CLTI after standard revascularization (at least 3 months after PTA or bypass) who were treated with re‐PTA were included in this group 1 (n = 43). Individuals with NO‐CLTI were treated either with ACT (group 2, n = 45) or conservatively (group 3, n = 42; Figure 1). There were no significant differences in baseline characteristics between the control and treatment groups (Table 1). During 2015–2017, there were temporary changes in the local and European regulatory guidelines when we could not undertake the ACT procedure; hence, patients seen in our foot clinic during this period formed the control group (conservative treatment was defined only as local dressing for gangrene and patient observation concerning those were NO‐CLTI). Specifically, the European Medicines Agency was reviewing the use of treatments involving human tissue and cell transplantation, as well as advanced therapy medicinal products. This review led to a suspension of cell therapy at our centre for 22 months. Consequently, patients who would have otherwise qualified for cell therapy during this time were instead assigned to the control group. However, patients in the control group did not differ in demographics, diabetes duration or complications compared to the other two groups.
FIGURE 1.
Scheme of the study.
The study was approved by the local ethics committee, and all patients gave written informed consent to take part in the study, which was carried out in accordance with the Declaration of Helsinki and Good Clinical Practice.
2.3. Follow‐up
The primary endpoint of the study was AFS. Secondary endpoints were overall survival, major amputation rates and a change in TcPO2 (as main ischaemia parameter). All patients were followed over 7 years, and no patients were lost to follow‐up. TcPO2 was assessed in non‐amputated patients.
2.4. Statistical analysis
Data are shown as percentages or mean ± SD. Statistical analyses were conducted using MEDCALC, BMDP Statistical Software Inc. 8.1 (Medcalc, Ostend, Belgium) and GRAPHPAD PRISM 10.1.2 (GraphPad Software, San Diego, CA, USA). Paired t‐tests, one‐way and two‐way ANOVA and Duncan's test were applied for group comparisons, with a significance threshold set at p < 0.05. The Kaplan–Meier curves were generated to assess AFS, amputation rates and overall survival, with log‐rank tests providing P values for comparisons. Hazard ratios (HRs) with 95% confidence intervals (CIs) were used to report group comparisons. Initially, a log‐rank test was conducted for all three groups, followed by pairwise comparisons. Additionally, separate log‐rank tests were performed for two groups at a time. For participants without reported events, their data were censored.
To compare the different therapeutic strategies for the CLTI, we used the net clinical benefit (NCB). This quantitative assessment estimates the balance between the positive outcome (a relevant increase in TcPO2 of more than 20 mm Hg) and the negative outcome (major amputation of the foot) that is associated with the treatment group.
To correct potential confounding factors a Cox proportional hazard model was performed where treatment type was the main predictor and all important baseline confounders (age, sex, diabetes duration, comorbidities and angiographic findings) were covariates.
3. RESULTS
Baseline demographic characteristics (age, sex, diabetes duration, diabetes control) or presence of comorbidities (ischaemic heart disease, hypertension, haemodialysis) did not differ between groups. Patients in ACT and control groups had significantly worse baseline angiograms in accordance with Graziani and GLASS (infrapopliteal region) classifications than re‐PTA group (both p<0.001), but there were no differences in baseline values of TcPO2 between groups (Table 1). Cox proportional hazard model showed no differences in baseline covariates (age, sex, diabetes duration and comorbidities); significant differences were found only in Graziani (adjusted HR 1.3, 95% CI 1.17–1.4) and GLASS (adjusted HR 1.25, 95% CI 1.11–1.34) stages.
The Kaplan–Meier estimation revealed that the primary endpoint—AFS in both active groups was significantly longer compared to control (both p < 0.001; Figure 2A), with no significant difference between ACT and re‐PTA groups (p = 0.06). A significant difference was observed between re‐PTA and control groups (HR 4.74 95% CI 2.63–8.53) as well as between ACT and control groups (HR 2.73 95% CI 1.65–4.53; Table 2).
FIGURE 2.
Primary and secondary endpoints in all three groups. (A) Amputation‐free survival, (B) rate of major amputation, (C) overall survival and (D) changes in TcPO2; ACT, autologous cell therapy (blue line), re‐PTA, repeated percutaneous transluminal angioplasty (green line), conservative control group (red line).
TABLE 2.
Amputation‐free survival, limb salvage and overall survival: Paired comparisons.
| ACT (n = 45) | re‐PTA (n = 43) | Control (n = 42) | |
|---|---|---|---|
| Amputation‐free survival | |||
| n/N (%) | 18/45 (40) | 26/43 (60.5) | 4/42 (9.5) |
| Hazard ratios | 0.56 (95% CI 0.31–1.03) a | 4.74 (95% CI 2.63–8.53) b | 2.73 (95% CI 1.65–4.53) c |
| Limb salvage | |||
| n/N (%) | 30/45 (66.6) | 31/43 (74.4) | 12/42 (28.6) |
| Hazard ratios | 0.73 (95% CI 0.33–1.6) a | 3.98 (95% CI 1.98–7.97) b | 2.9 (95% CI 1.55–5.41) c |
| Overall survival | |||
| n/N (%) | 22/45 (48.9) | 29/43 (67.4) | 14/42 (33.3) |
| Hazard ratios | 0.56 (95% CI 0.29–1.08) a | 2.97 (95% CI 1.56–5.65) b | 1.69 (95% CI 0.98–2.93) c |
Abbreviations: ACT, autologous cell therapy; CI, confidence intervals; HR, hazard ratio.
ACT vs. re‐PTA.
re‐PTA vs. control.
ACT vs. control.
We observed similar results with limb salvage—over 7 years the amputation rate was significantly lower in ACT and re‐PTA groups in comparison with the control group (both p < 0.001; Figure 2B) without a difference between both active groups (p = 0.43). Limb salvage hazard ratio for re‐PTA vs. control was 3.98 (95% CI 1.98–7.97) and for ACT vs. control was 2.9 (95% CI 1.55–5.41; Table 2).
Re‐PTA group showed significantly longer overall survival compared to the control group (HR 2.97 95% CI 1.56–5.65; p < 0.001), and no difference compared to the ACT group (HR 0.56 95% CI 0.29–1.08; p = 0.081), as well there was no difference between ACT and control groups (HR 1.69 95% CI 0.98–2.93; p = 0.063; Figure 2C, Table 2).
TcPO2 increased significantly in both active groups (ACT and re‐PTA) at 6 months (both p < 0.001) in comparison with baseline values, and this increase persisted for the whole follow‐up period. On the other hand, no significant change in TcPO2 was seen in the control group (Figure 2D).
We observed the NCB in the re‐PTA group of 0.65, which was slightly better than in the ACT group (0.57); the NCB in the control group was −0.71. Both the re‐PTA group and the ACT group had significantly better NCB than the control group (1.36 and 1.28, respectively); the difference between both active groups was very small (0.08; Table 3).
TABLE 3.
Net clinical benefit (NCB) of the treatment groups.
| Parameter | ACT (n = 45) | re‐PTA (n = 43) | Control (n = 42) |
|---|---|---|---|
| Positive outcome—increase in TcPO2 of more than 20 mm Hg | 41/45 (0.91) | 40/43 (0.93) | 0/42 (0) |
| Negative outcome—major amputation | 15/45 (0.33) | 12/43 (0.28) | 30/42 (0.71) |
| NCB | 0.91–0.33 = 0.57 | 0.93–0.28 = 0.65 | 0–0.71 = −0.71 |
| ACT vs. Control | 0.57–(−0.71) = 1.28 | ||
| ACT vs. PTA | 0.57–0.65 = −0.08 | ||
| PTA vs. Control | 0.65–(−0.71) = 1.36 | ||
4. DISCUSSION
This is the first study to report on long‐term follow‐up in patients with CLTI treated by re‐PTA or ACT and retrospectively compares the treatment options for those with NO‐CLTI. We have shown that ACT compared to conservative treatment led to more limbs saved, longer AFS, but did not significantly improve overall survival. Even though there was a trend to longer overall survival in ACT compared to the control group, the difference was not significant (p = 0.063). The main goal of ACT is to improve limb ischaemia to achieve limb salvage or heal the chronic wound and we have demonstrated in this long‐term follow‐up study that AFS and limb salvage can be improved following ACT. Moreover, people with CLTI and diabetes are usually diagnosed with general atherosclerosis and even if their limb ischaemia is improved by the ACT, they can still die mostly as a result of cardiovascular or cerebrovascular events, especially during a long follow‐up.
In our previous study, we demonstrated that a 12‐month AFS between re‐PTA and ACT was similar and significantly longer than in the control group 20 ; in our present study, we highlight the long‐term efficacy of cell therapy during a 7‐year follow‐up.
PTA is currently an acceptable first‐line treatment for selected patients with CLTI. In patients with CLTI resulting in foot ulceration, four clinical studies assessed the efficacy of PTA that was performed in adjunctive fashion to the delivery of ACT, and one study compared both treatment options individually. Tian et al. reported improved efficacy and reduced restenosis with combination treatment compared to either PTA or ACT alone. 21 Similarly, intramuscular injection of human umbilical cord‐derived mesenchymal stem cells combined with PTA led to improved ABI, claudication distance and TcPO2 compared to PTA alone. 22 The major advantage of ACT over PTA is that it is able to directly affect microcirculation by inducing therapeutic arteriogenesis—a maturation of pre‐existing smaller collaterals in the ischaemic tissue that leads to a significant improvement in skin blood flow even though the major arteries are completely obturated.
The safety and efficacy of ACT have been demonstrated in several trials and meta‐analyses 13 , 17 , 23 including our own short‐term randomized controlled trial. 24 Most of the studies conclude that ACT improves ischaemia parameters such as ABI or TcPO2, enhances wound healing and reduces limb pain, but the results for the reduction of major amputation rate or AFS are mixed. Even though the efficacy of ACT on limb ischaemia has been proven, the real impact on limb salvage still remains unclear. Despite the promising results, the efficacy of ACT on the prevention of major amputation and AFS is not universally established. While some randomized controlled trials have shown benefits 13 , 25 others have failed to demonstrate significant improvements in AFS. 15 , 26 The recently published randomized controlled trial PACE included 213 patients who were randomized 2:1 to receive either mesenchymal allogeneic placental expanded cells or placebo. This study showed no significant difference in AFS, major amputation rates or healing of chronic wounds in the whole cohort. However, the beneficial effect of mesenchymal allogeneic placental expanded cells was recognized in individuals without diabetes or those with well‐controlled diabetes (HbA1c below 6.5%). The main drawback of this study was the definition of CLTI; ankle pressure below 70 mm Hg and toe pressure below 50 mm Hg, which is not an accepted definition of CLTI according to guidelines. 26
An Italian study by Meloni et al. demonstrated that 1‐year limb salvage after 3 cycles of peripheral blood mononuclear cell (PBMNC) therapy in 55 people with CLTI was 89.1%. 27 The main difference from our study was that the Meloni study had no control group, much shorter follow‐up, and included older patients (mean age 74.8 years). Other important differences were in the cell source (peripheral blood vs. bone marrow) and repeated injection of PBMNC (3 times every 21–42 days), whereas in our study we administered cell therapy only once.
The efficacy of ACT may also be influenced by factors such as cell types, source, administration route and dosage, which vary across studies. 28 The ESC Guidelines (2017) did not recommend ACT as a treatment of CLTI (grade 3B), whereas there was a shift in 2019 in the Global Vascular Guidelines which recommended restricting the use of ACT to registered clinical trials (grade 1B). The latest 2024 ESC Guidelines for PAD did not mention ACT in their recommendations even though there has been more recent data to support the evidence. The latest Cochrane analysis assessing the efficacy of ACT on CLTI concluded that there is low‐certainty evidence, even though they evaluated only 4 RCTs with a total of 176 participants. 29
The RESTORE‐CLI trial demonstrated a significantly longer time to treatment failure (defined as major amputation, death or worsening of the ulcer) in the ACT group compared to placebo. 12 In our randomized controlled trial, we observed significant improvements in wound healing and TcPO2 levels after 12 weeks of ACT treatment compared to standard therapy. 24 On the other hand, the PACE study, a large phase III trial, found no significant difference in AFS between patients treated with placental‐derived cell therapy and placebo, 26 except the subgroup of diabetic people with lower HbA1c that showed a significant improvement.
In order to establish the efficacy of ACT for limb salvage in CLTI, we need larger, well‐designed RCTs and longer follow‐up to validate the promising results seen in smaller studies. Moreover, standardization of cell therapy protocols, including cell types, administration methods and dosages, could help produce more consistent and comparable results. We believe that long‐term follow‐up studies are crucial to assess the durability of ACT's effects on limb salvage, as we showed in our current retrospective comparative controlled trial with a follow‐up of 7 years. Another important point could be a subgroup analysis that may help identify patient populations most likely to benefit from ACT, such as those with well‐controlled diabetes. 26
The question arises whether ACT could also be beneficial for patients with moderate limb ischaemia, either as a standalone treatment or in combination with standard revascularization. This represents a shift in the current approach to cell therapy indications; so far, this therapy has been indicated only for patients with NO‐CLTI who are not candidates for other forms of revascularization. However, as we showed in our current long‐term follow‐up study, these patients have a very high risk of cardiovascular complications and relatively high mortality; consequently, improving limb ischaemia with ACT may not necessarily improve survival unless other risk factors for atherosclerosis are addressed or if cardiovascular disease is already at an advanced stage. 30
5. LIMITATIONS
We are aware that our study has several limitations that may affect the broader applicability of our findings. The study was retrospective and not a randomized controlled trial. Even though there was no significant difference in baseline characteristics, Rutherford scores and TcPO2, patients in the PTA group had significantly less severe angiographic findings, which could cause a selection bias. We did not perform a propensity‐scored matched case–control study to reduce the selection bias; on the other hand, the Cox proportional hazard model was done. During a retrospective study, data are collected after the outcomes have occurred, often relying on medical records, which could cause an information bias. In a retrospective study, the researchers have usually limited control over the variables and cannot influence how the data were originally collected, which limits the ability to adjust for all relevant factors. Also, the decision to perform either PTA or ACT (in case the patient was assigned as ‘no‐option’) was often based on technical issues of PTA (inability to perform the standard revascularization) or other comorbid conditions.
On the other hand, we laid out well‐designed inclusion criteria and very long follow‐up of our study in a centre that has more than 17 years of experience with ACT and our foot clinic is a level 3 foot centre for the whole of the Czech Republic and offers very comprehensive DFU care.
6. CONCLUSION
Our retrospective study suggests lower amputation rates and longer AFS in patients treated by ACT and re‐PTA in contrast to patients treated conservatively. Overall survival was significantly longer only in the re‐PTA group. ACT, in accordance with our results, seems to be effective in the long term, especially on limb salvage in those with diabetes and NO‐CLTI. Larger randomized controlled trials are urgently needed to confirm our preliminary findings and provide an important treatment option for patients with NO‐CLTI.
FUNDING INFORMATION
Supported by the project CarDia (Programme EXCELES, Project No. LX22NPO5104)—Funded by the European Union – Next Generation EU.
CONFLICT OF INTEREST STATEMENT
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
PEER REVIEW
The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer‐review/10.1111/dom.16510.
ACKNOWLEDGEMENTS
None.
Dubský M, Sojáková D, Husáková J, et al. Long‐term efficacy of autologous cell therapy, repeated PTA and conservative treatment in people with diabetes and chronic limb‐threatening ischaemia. Diabetes Obes Metab. 2025;27(9):4729‐4736. doi: 10.1111/dom.16510
DATA AVAILABILITY STATEMENT
Data available on request due to privacy/ethical restrictions.
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Data Availability Statement
Data available on request due to privacy/ethical restrictions.