Abstract
Objectives:
The prevalence of chronic limb-threatening ischemia (CLTI) has increased alongside rising rates of diabetes mellitus (DM). While diabetic patients with CLTI have worse outcomes compared to patients without diabetes, conflicting data exist on the relationship between the severity of DM and CLTI outcomes. Close inspection of the relationship between DM severity and outcomes in CLTI may benefit surgical decision-making and patient education.
Methods:
We retrospectively reviewed patients who received endovascular intervention or surgical bypass for CLTI at our multidisciplinary Limb Preservation Program (LPP) from 2013–2019 to collect patient characteristics using SVS reporting standards, arterial lesion characteristics from recorded angiograms, and outcomes, including survival, amputation, wound healing, and revascularization patency. Controlled DM was defined as SVS Grade 1 (controlled, not requiring insulin) and Grade 2 (controlled, requiring insulin), while uncontrolled DM was defined as SVS Grade 3 (uncontrolled), and DM severity was assessed using pre-operative hemoglobin A1c (HgbA1c) values. Product-limit Kaplan-Meier was used to estimate survival functions. Univariable Cox proportional hazards analyses guided variable selection for multivariable analyses.
Results:
Our LPP treated 177 limbs from 141 patients with DM. Patients with uncontrolled DM were younger (60.44 ± 10.67 vs 65.93 ± 10.89 years old, p=0.0009) and had higher HgbA1c values (8.97 ± 1.85% vs 6.79 ± 1.10%, p<0.0001). Fewer patients with uncontrolled DM were on dialysis compared to patients with controlled DM (15.6% vs 30.9%, p=0.0278). By Kaplan-Meier analysis, DM control did not affect time to mortality, limb salvage, wound healing, or loss of patency. However, multivariable proportional hazards analysis demonstrated increased risk of limb loss in patients with increasing HgbA1C (HR=1.96 [1.42–2.80], p<0.0001) or dialysis dependence (HR=15.37 [3.44–68.73], p=0.0003), increased risk of death in patients with worsening pulmonary status (HR=1.70 [1.20–2.39], p=0.0026), and increased risk of delayed wound healing in patients who are male (HR=0.48 [0.29–0.79], p=0.0495). No independent association existed between loss of patency with any of the variables we collected.
Conclusions:
Patients with uncontrolled DM, as defined by SVS reporting standards, do not have worse outcomes following revascularization for CLTI compared to patients with controlled DM. However, increasing HgbA1c is associated with a greater risk for early amputation. Prior to revascularization, specific attention to the level of glycemic control in patients with DM is important, even if DM is “controlled.” In addition to aggressive attempts at improved glycemic control, those with elevated HgbA1c should receive careful education regarding their increased risk of amputation despite revascularization. Future work is necessary to incorporate the severity of DM into risk models of revascularization for the CLTI population.
Keywords: CLTI, CLI, Revascularization, Diabetes, Diabetes Severity
Introduction
Chronic limb-threatening ischemia (CLTI) is the most severe form of peripheral artery disease (PAD) and has become increasingly prevalent due to the aging population and the diabetes mellitus (DM) epidemic.1–3 Patients with CLTI experience extremely high mortality and amputation rates.1,4–7 In addition to medical therapy to reduce cardiovascular risk, surgical or endovascular revascularization is critical for limb salvage.1,4,8,9
Many comorbid conditions affect the risk of developing CLTI and may influence limb salvage after revascularization, including hypertension (HTN), hyperlipidemia (HLD), chronic kidney disease (CKD), and DM.2,3,5,10–14 However, risk-benefit prediction models utilized by surgeons considering revascularization are often based solely on the presence or absence of certain comorbidities.15–17 For instance, while the presence of DM is a well-documented risk factor, the extent to which DM severity aggravates outcomes is less clear.15,16,18–21 The unclear role of DM severity on outcomes in CLTI may be partially attributed to heterogeneous definitions of DM control (e.g., diet alone, oral antihyperglycemic medications, insulin, etc.) or failure to use quantitative measures of hyperglycemia (e.g., hemoglobin A1c, HgbA1c) while controlling for atherosclerotic disease severity.8,22–24 To provide additional clarity on the impact of DM severity on outcomes in CLTI, we investigated survival, limb salvage, wound healing, and patency in patients with CLTI and DM as defined by both SVS reporting standards and HgbA1c.
Methods
After approval from an Institutional Review Board (The Ohio State University Biomedical Sciences Institutional Review Board protocol number 2019H0219), a retrospective cohort study was conducted among patients with CLTI who received endovascular intervention or surgical bypass at our multidisciplinary Limb Preservation Program (LPP) from 2013 to 2019. Our LPP team consists of vascular surgery, podiatry, and a fully staffed wound center providing both inpatient and outpatient care at a single location, as previously described.25 The Program is purposefully located in a community with high rates of renal failure, diabetes mellitus, and CLTI.
The initial decision to pursue revascularization in a patient was made by a vascular surgeon in conjunction with input from an LPP podiatrist regarding salvageability based on tissue loss and functionality of potential foot reconstruction. Patient functional status and angiographic or surgical risk also informed the decision to revascularize or perform primary amputation. Neither DM control nor HgbA1c levels independently disqualified patients from revascularization, though perioperative hyperglycemia and electrolyte abnormalities were addressed prior to proceeding with surgery.
Patient information was collected according to Society for Vascular Surgery (SVS) reporting standards.26 Controlled DM was defined as SVS Grades 1 and 2 while uncontrolled DM was defined as SVS Grade 3 (Grade 1: controlled, not requiring insulin, Grade 2: controlled by insulin, Grade 3: uncontrolled or Type 1 DM). “Controlled” means that with treatment the patient achieved normoglycemia or a HgbA1c < 7.0, and “uncontrolled” means that the patient was unable to achieve normoglycemia or a HgbA1c < 7.0.27 DM severity was assessed with pre-operative HgbA1c values (%). Lesion characteristics, including anatomic location of disease (aortoiliac, femoropopliteal, and tibial), total lesion length, and the presence of a chronic total occlusion (CTO), were measured from angiograms at the time of intervention for limbs treated endovascularly or from diagnostic angiograms for patients who received a bypass as the index intervention. Technical failure of endovascular intervention was defined as the inability to restore in-line flow to the affected foot for anterior and posterior tibial targets, the inability to restore in-line flow to the ankle for peroneal targets, or residual (>50%) stenosis after intervention along the target arterial path.25,26 Success of surgical bypass was defined as restoration of in-line flow via bypass grafting with or without concomitant endarterectomy as needed to the affected foot for anterior and posterior tibial targets or the ankle for peroneal targets, and without residual (>50%) stenosis along the target arterial path on completion angiography including images of inflow, anastomoses, conduit, and outflow.
Primary outcomes included time to death, limb loss, wound healing, and loss of patency. Limb loss was defined as any above-ankle amputation. Evidence-based Wound Healing Society protocols were used in the treatment of all patients.28 All patients were seen for wound care every two-to-four weeks until healed. Vascular clinical and noninvasive arterial examinations occurred every three months for the first year after revascularization. After the first year, vascular follow-up occurred every six months with noninvasive arterial assessment. Loss of patency was defined as a loss of a previously palpable pedal pulse, a velocity ratio >2.5 on arterial duplex, a drop in ABI of >0.15, or when repeat intervention was performed in the target arterial path.
Two-sample independent t-tests were used to compare continuous variables (shown as mean ± standard deviation), and Chi-squared or Fisher’s exact tests were used for categorical variables (shown as category counts and percentages). Product-limit Kaplan-Meier was used to estimate survival functions. Between-group comparisons were also made using univariable Cox proportional hazards analysis, and variables with a p-value less than 0.2, along with age, sex, WIfI stage, and index intervention type (endovascular or open surgical bypass), were included in a multivariable analysis to determine hazard ratios (HRs) for patient characteristics with respect to time to death, limb loss, wound healing, and loss of patency. For the proportional hazards analyses, cardiac status, pulmonary status, and WIfI stage were treated as ordinal variables while age, HgbA1c, and lesion length were treated as continuous variables such that HRs for all of these variables indicate risk for each 1-unit incremental increase. All analyses were performed at an alpha level of 0.05 using R Studio (version 4.2.2).
Results
Our multidisciplinary LPP revascularized 223 limbs from 198 unique patients between 2013 and 2019. Of these 223 total revascularized limbs, 177 limbs were from 141 patients with DM. Of these 177 revascularized limbs from patients with DM, 144 limbs received endovascular intervention, and 33 limbs received surgical bypass. In the same period, 128 limbs from 118 patients were prescribed primary amputation. The distribution of DM control in the revascularized and primary amputation populations was not different (No DM: 19.9% vs 28.7%; SVS Grade 1: 16.7% vs 14.1%; Grade 2: 22.2% vs 18.8%; and Grade 3: 41.2% vs 37.5% in revascularization vs amputation populations, respectively; p=0.2220). Additionally, the presence of DM was not different among patients who experienced technical failure versus technical success of endovascular intervention (66.7% vs 80.0%, p=0.1021), and all open bypasses were successful.
Our cohort of 141 patients with DM had a mean age of 63 years, 64% were male, 58% were White, 41% were Black, the mean HgbA1c was 8.0%, 33% were current smokers, 89% had HTN, 22% were dependent on dialysis due to CKD, 89% had HLD, and 55% had a WIfI risk of amputation stage of 3 or 4. Regarding the level of atherosclerotic disease in the 177 revascularized limbs, 9% had aortoiliac disease, 77.4% had femoropopliteal disease, 47% had tibial disease (31.1% of patients had multi-level disease). The mean total lesion length was 17.9 cm, and 52.5% of limbs had a CTO. The index intervention was endovascular in 81.4% of treated limbs, and the remaining limbs were treated with open bypass. Patients were followed for 34 ± 21 months (mean ± standard deviation). During the study period, 43 patients died, 21 limbs required an above-ankle amputation, and 44 revascularizations lost patency as defined previously.
Of the 177 revascularized limbs from patients with DM, 91 limbs were from patients with uncontrolled DM (Table I). All patients with uncontrolled DM (SVS Grade 3) had Type 2 DM. Patients with uncontrolled DM were younger than those with controlled DM (60.44 ± 10.67 vs 65.93 ± 10.89, p=0.0009), had a higher mean HgbA1c (8.97 ±1.85% vs 6.79 ± 1.10%, p<0.0001), and fewer required hemodialysis (15.6% vs 30.9%, p=0.0278). No differences were noted when grouped by sex, ethnicity, smoking status, HTN, HLD, cardiac status, pulmonary status, WIfI stage, level of disease, lesion length, the presence of CTO, or index intervention.
Table I. Characteristics of Patients with Diabetes Mellitus.
Characteristics of patients with DM and CLTI that underwent revascularization are shown, stratified by SVS DM Grade. Patients with unknown characteristics were excluded from applicable denominators. A “*” denotes a statistically significant difference between groups (p<0.05). A “†” denotes a group was excluded from analysis. A “‡” denotes reporting according to SVS standards.
| Patient Characteristic | Controlled Diabetes Mellitus (N=86) | Uncontrolled Diabetes Mellitus (N=91) | p-value |
|---|---|---|---|
| Age | 65.93 ± 10.89 | 60.44 ± 10.67 | 0.0009* |
| Male Sex | 57 (66.3%) | 57 (62.6%) | 0.7273 |
| Ethnicity | 0.4106 | ||
| White | 53 (62.4%) | 49 (53.8%) | |
| Black | 32 (37.6%) | 40 (44%) | |
| Other† | 0 (0%) | 2 (2.2%) | |
| Hemoglobin A1c (%) | 6.79 ± 1.10 | 8.97 ± 1.85 | <0.0001* |
| Current smoker | 26 (31%) | 32 (35.6%) | 0.6293 |
| Hypertension | 73 (92.4%) | 85 (93.4%) | 0.4269 |
| Dialysis | 25 (30.9%) | 14 (15.6%) | 0.0278* |
| Hyperlipidemia | 77 (90.6%) | 80 (88.9%) | 0.9932 |
| Cardiac Status‡ | 0.1191 | ||
| Grade 1 | 19 (22.1%) | 35 (38.9%) | |
| Grade 2 | 8 (9.3%) | 7 (7.8%) | |
| Grade 3 | 43 (50%) | 35 (38.9%) | |
| Grade 4 | 16 (18.6%) | 13 (14.4%) | |
| Pulmonary Status‡ | 0.3119 | ||
| Grade 1 | 53 (63.1%) | 69 (75.8%) | |
| Grade 2 | 11 (13.1%) | 9 (9.9%) | |
| Grade 3 | 13 (15.5%) | 9 (9.9%) | |
| Grade 4 | 7 (8.3%) | 4 (4.4%) | |
| SVS WIfI | 0.3585 | ||
| Stage 1 | 8 (11.8%) | 13 (16%) | |
| Stage 2 | 15 (22.1%) | 16 (19.8%) | |
| Stage 3 | 16 (23.5%) | 27 (33.3%) | |
| Stage 4 | 29 (42.6%) | 25 (30.9%) | |
| Level of Disease | |||
| Aortoiliac | 6 (7.0%) | 10 (11.0%) | 0.5040 |
| Femoropopliteal | 70 (81.4%) | 67 (73.6%) | 0.2912 |
| Tibial | 37 (43.0%) | 46 (50.5%) | 0.3941 |
| Multi-level | 26 (30.2%) | 29 (31.9%) | 0.8142 |
| Lesion Length (cm) | 20.41 ± 16.20 | 17.97 ± 15.88 | 0.3291 |
| CTO Present | 29 (41.4%) | 32 (43.2%) | 0.9003 |
| Index Intervention | 1.0000 | ||
| Endovascular | 70 (81.4%) | 74 (81.3%) | |
| Bypass | 16 (18.6%) | 17 (18.7%) |
Continuous variables shown as mean ± standard deviation.
Statistically significant difference between groups (p<0.05).
Excluded from analysis.
Reported according to SVS standards.28
After the index intervention, survival (52.5 ± 2.4 vs 53.1 ± 2.6 months, p=0.7420), limb salvage (58.2 ± 2.1 vs 59.2 ±2.1 months, p=0.6660), wound healing (28.1 ± 3.4 vs 19.9 ± 3.0 months, p=0.0840), and patency (50.1 ± 3.1 vs 43.2 ± 3.7 months, p=0.2470) were not different between patients with uncontrolled versus controlled DM (Figure 1).
Figure 1.
Kaplan-Meier plots are shown for the primary outcomes of patients with DM and CLTI after revascularization: survival (A), limb salvage (B), wound healing (C), and patency (D). Functions are grouped by severity of DM: patients with controlled DM (CDM; SVS Grades 1 and 2) shown in dashed green and patients with uncontrolled DM (SDM; SVS Grade 3) shown in solid blue. Censored values are shown with “+”. Curves are truncated where standard error exceeded 10%. Survival (p=0.7420), limb salvage (p=0.6660), wound healing (p=0.0840), and patency (p=0.2470) were not different between CDM and SDM patients.
Univariable and multivariable proportional hazards analyses were performed to determine associations between the variables we collected and time to death and time to limb loss (Table II). Univariable analysis showed worsening cardiac (HR=1.42 [1.06–1.90], p=0.0174) and pulmonary (HR=1.85 [1.42–2.41], p<0.0001) status were associated with earlier time to death. Based on a univariable p < 0.2, ethnicity, dialysis dependence, cardiac status, pulmonary status, and the presence of a CTO were included along with the predetermined variables (age, sex, WIfI stage, and index intervention) in the multivariable analysis, which showed that only pulmonary status was independently associated with earlier time to death (HR=1.70 [1.20–2.39], p=0.0026).
Table II. Univariable and Multivariable Cox Proportional Hazards Analysis of Predictors of Survival and Limb Loss.
Hazard ratios and 95% confidence intervals (HR [95% CI]) from Cox proportional hazards analysis are shown for survival and limb loss in patients with DM and CLTI. Reference rows (Ref.) and categories with insufficient number of events to produce a HR (Insuf.) are noted. Variables with p<0.2 on univariable analysis, along with age, sex, WIfI stage, and index intervention (endovascular or bypass), were included in the multivariable analysis. Characteristics with a p<0.05 on univariable or multivariable analysis are noted with a “†”.
| Survival | Limb Loss | |||||||
|---|---|---|---|---|---|---|---|---|
| Characteristic | Univariable HR | p-value | Multivariable HR | p-value | Univariable HR | p-value | Multivariable HR | p-value |
| Age* | 1.00 [0.97–1.03] | 0.9614 | 0.99 [0.96–1.03] | 0.7406 | 1.01 [0.97–1.05] | 0.5299 | 1.02 [0.97–1.08] | 0.4127 |
| Male Sex | 1.35 [0.71–2.59] | 0.3637 | 1.28 [0.59–2.81] | 0.532 | 0.92 [0.38–2.23] | 0.8600 | 1.34 [0.44–4.06] | 0.6017 |
| Ethnicity | ||||||||
| White | Ref. | - | - | - | - | - | - | - |
| Black | 0.58 [0.30–1.12] | 0.1038 | 0.64 [0.30–1.36] | 0.2456 | 1.08 [0.45–2.57] | 0.8605 | - | - |
| Uncontrolled DM | 1.11 [0.61–2.02] | 0.7404 | - | - | 1.20 [0.51–2.85] | 0.6779 | - | - |
| Hemoglobin A1c (%)* | 1.09 [0.91–1.31] | 0.3617 | - | - | 1.39 [1.11–1.75] | 0.0049† | 1.96 [1.42–2.70] | <0.0001† |
| Current smoker | 0.82 [0.42–1.60] | 0.5621 | - | - | 0.32 [0.09–1.09] | 0.0692 | 0.33 [0.08–1.44] | 0.1409 |
| Hypertension | 2.34 [0.32–17.04] | 0.4012 | - | - | 1.20 [0.16–9.00] | 0.8590 | - | - |
| Hyperlipidemia | 0.64 [0.27–1.52] | 0.3108 | - | - | 2.28 [0.31–17.04] | 0.4206 | - | - |
| Dialysis | 1.7 [0.90–3.22] | 0.1027 | 1.59 [0.70–3.59] | 0.2671 | 3.42 [1.45–8.05] | 0.0050† | 15.37 [3.44–68.73] | 0.0003† |
| Cardiac Status* | 1.42 [1.06–1.90] | 0.0174† | 0.98 [0.68–1.42] | 0.9214 | 1.07 [0.72–1.58] | 0.7440 | - | - |
| Pulmonary Status* | 1.85 [1.42–2.41] | <0.0001† | 1.70 [1.20–2.39] | 0.0026† | 0.84 [0.50–1.42] | 0.5222 | - | - |
| WIfI Stage* | 1.09 [0.79–1.51] | 0.6030 | 1.1 [0.78–1.55] | 0.6055 | 0.82 [0.54–1.24] | 0.3477 | 0.65 [0.39–1.07] | 0.0879 |
| Aortoiliac Disease | 1.01 [0.36–2.82] | 0.9874 | - | - | 0.51 [0.07–3.79] | 0.5093 | - | - |
| Femoropopliteal Disease | 1.32 [0.61–2.84] | 0.4806 | - | - | 1.87 [0.55–6.35] | 0.3163 | - | - |
| Tibial Disease | 0.69 [0.37–1.28] | 0.2355 | - | - | 1.61 [0.68–3.83] | 0.2804 | - | - |
| Lesion Length (cm) * | 1.00 [0.98–1.02] | 0.9920 | - | - | 1.00 [0.97–1.03] | 0.9495 | - | - |
| CTO Present | 0.62 [0.34–1.14] | 0.1271 | 0.65 [0.3–1.43] | 0.2856 | 1.23 [0.52–2.93] | 0 .6377 | - | - |
| Index Intervention | ||||||||
| Endovascular | Ref. | - | - | - | - | - | - | - |
| Bypass | 0.54 [0.21–1.37] | 0.1940 | 0.90 [0.26–3.09] | 0.8688 | 0.19 [0.03–1.44] | 0.1086 | 0.65 [0.08–5.56] | 0.6959 |
Analyzed incrementally.
p<0.05
Univariable analysis showed HgbA1c (HR=1.39 [1.11–1.75], p=0.0049) and dialysis dependence (HR=3.42 [1.45–8.05], p=0.0050) were associated with earlier time to limb loss. Based on a univariable p < 0.2, HgbA1c, smoking status, and dialysis dependence were included along with the predetermined variables in the multivariable analysis, which showed that both HgbA1c (HR=1.96 [1.42–2.70], p<0.0001) and dialysis dependence (HR=15.37 [3.44–68.73], p=0.0003) were independently associated with earlier time to limb loss.
Univariable and multivariable proportional hazards analysis were performed to determine associations between the variables we collected and time to wound healing and loss of patency (Table III). Univariable analysis did not identify any associations between our collected variables and time to wound healing. Based on a univariable p < 0.2, uncontrolled DM, dialysis dependence, hyperlipidemia, and presence of aortoiliac disease were included along with the predetermined variables in the multivariable analysis, which showed that male sex (HR=0.48 [0.29–0.79], p=0.0036) was associated with later time to wound healing.
Table III. Univariable and Multivariable Cox Proportional Hazards Analysis of Predictors of Wound Healing and Patency.
Hazard ratios and 95% confidence intervals (HR [95% CI]) from Cox proportional hazards analysis are shown for wound healing and patency in patients with DM and CLTI. Reference rows (Ref.) and categories with insufficient number of events to produce a HR (Insuf.) are noted. Variables with p<0.2 on univariable analysis, along with age, sex, WIfI stage, and index intervention (endovascular or bypass), were included in the multivariable analysis. Characteristics with a p<0.05 on univariable or multivariable analysis are noted with a “†”.
| Wound Healing | Patency | |||||||
|---|---|---|---|---|---|---|---|---|
| Characteristic | Univariable HR | p-value | Multivariable HR | p-value | Univariable HR | p-value | Multivariable HR | p-value |
| Age* | 1.01 [0.99–1.03] | 0.3603 | 1.00 [0.98–1.03] | 0.6966 | 1.02 [0.99–1.05] | 0.2159 | 1.02 [0.99–1.05] | 0.1345 |
| Male Sex | 0.75 [0.49–1.14] | 0.1804 | 0.48 [0.29–0.79] | 0.0036† | 2.03 [1.01–4.11] | 0.0495† | 1.88 [0.87–4.07] | 0.1072 |
| Ethnicity | ||||||||
| White | Ref. | - | - | - | - | - | - | - |
| Black | 1.03 [0.68–1.56] | 0.8863 | - | - | 0.67 [0.36–1.25] | 0.2051 | - | - |
| Other | 1.75 [0.24–12.68] | 0.5819 | - | - | Insuf. | - | - | - |
| Uncontrolled DM | 0.71 [0.47–1.06] | 0.0950 | 0.62 [0.37–1.05] | 0.0757 | 0.70 [0.39–1.28] | 0.2489 | - | - |
| Hemoglobin A1c (%)* | 1.05 [0.93–1.19] | 0.4343 | - | - | 1.09 [0.92–1.30] | 0.2926 | - | - |
| Current smoker | 1.01 [0.65–1.58] | 0.9692 | - | - | 0.70 [0.35–1.39] | 0.3088 | - | - |
| Hypertension | 1.15 [0.46–2.83] | 0.7652 | - | - | 2.69 [0.37–19.56] | 0.3295 | - | - |
| Hyperlipidemia | 0.64 [0.34–1.21] | 0.1690 | 0.82 [0.41–1.67] | 0.0977 | 0.71 [0.30–1.67] | 0.4306 | - | - |
| Dialysis | 1.49 [0.93–2.37] | 0.0962 | 1.59 [0.92–2.77] | 0.5861 | 1.72 [0.90–3.31] | 0.1020 | 2.08 [0.98–4.41] | 0.0572 |
| Cardiac Status* | 0.98 [0.82–1.18] | 0.8693 | - | - | 1.07 [0.82–1.41] | 0.6074 | - | - |
| Pulmonary Status* | 0.93 [0.74–1.19] | 0.5805 | - | - | 0.76 [0.52–1.12] | 0.1650 | 0.73 [0.48–1.11] | 0.1351 |
| WIfI Stage* | 0.90 [0.73–1.09] | 0.2739 | 0.83 [0.67–1.03] | 0.0861 | 1.07 [0.78–1.46] | 0.6786 | 1.04 [0.74–1.45] | 0.8192 |
| Aortoiliac Disease | 1.60 [0.83–3.10] | 0.1590 | 1.62 [0.77–3.41] | 0.2023 | 0.51 [0.12–2.10] | 0.3488 | - | - |
| Femoropopliteal Disease | 0.83 [0.52–1.32] | 0.4273 | - | - | 1.31 [0.61–2.83] | 0.4862 | - | - |
| Tibial Disease | 0.91 [0.61–1.37] | 0.6526 | - | - | 1.27 [0.70–2.29] | 0.4299 | - | - |
| Lesion Length (cm) * | 1.00 [0.99–1.01] | 0.9196 | - | - | 1.01 [0.99–1.03] | 0.2449 | - | - |
| CTO Present | 1.03 [0.69–1.55] | 0.8821 | - | - | 1.15 [0.63–2.09] | 0.6475 | - | - |
| Intervention | ||||||||
| Endovascular | Ref. | - | - | - | - | - | - | - |
| Bypass | 1.35 [0.83–2.19] | 0.2305 | 1.52 [0.86–2.70] | 0.1534 | 0.82 [0.38–1.77] | 0.6130 | 0.81 [0.33–2.04] | 0.6590 |
Analyzed incrementally.
p<0.05
Univariable analysis showed male sex (HR=2.03 [1.01–4.11], p=0.0495) was associated with earlier time to loss of patency. Based on a univariable p < 0.2, dialysis dependence and pulmonary status were included along with the predetermined variables in the multivariable analysis, which did not identify any independent associations with time to loss of patency.
Discussion
The role of DM in the pathogenesis of vascular disease is well-established and mediated through an increase in advanced glycosylation end products and reactive oxygen species.26,29 CLTI patients with DM generally have worse outcomes than the non-diabetic CLTI population, although mixed results exist.12,16,19–21,30,31 However, within the diabetic CLTI population, few studies have examined the impact of different degrees of glycemic control on post-revascularization outcomes.22,32
In our cohort, patients with uncontrolled DM (SVS Grade 3) were younger, had higher HgbA1c values, and fewer were dialysis-dependent compared to their controlled DM counterparts (SVS Grades 1 and 2). SVS Grade of DM control was not associated with primary outcomes (survival, limb salvage, wound healing, and patency) on Kaplan-Meier analysis. However, multivariable proportional hazards analysis demonstrated an increased risk of limb loss in patients with increasing HgbA1c or dialysis dependence. Furthermore, we found an increased risk of death in patients with worsening pulmonary status, a decreased risk of early wound healing in male patients, and no association between loss of patency with any of the variables we collected.
Our results on mortality and limb salvage agree with those of a 2010 retrospective study on revascularization outcomes in a Japanese CLTI population done by Takahara et. al.22 Takahara identified an increased risk of major amputation with each 1% increase in HgbA1C (HR= 1.35) but did not find any association between HgbA1C and mortality, similar to what we report here.22 Importantly, both studies agree dialysis dependence confers an increased risk of amputation in patients with DM. While we did not identify any differences in patency across DM severity, a 2018 study in CLTI patients with DM noted an increased risk of clinically significant restenosis requiring reintervention in patients with an elevated HgbA1C.32 Clearly, there is a need for more studies examining the impact of glycemic control in this population to develop an understanding of the role DM severity has on primary outcomes.
Intense glycemic control has shown benefits for reducing amputation rates compared to standard approaches in the general PAD population.8,24,33 Thus, while CLTI patients with severe DM should not be denied revascularization in the presence of acceptable operative risk, intense glycemic control is advised to improve overall outcomes. Furthermore, given that risk adjustment in our data uncovered some role for DM severity (i.e., HgbA1c) in regulating the risk of early amputation, combinations of risk factors for poor outcomes after revascularization, including diabetes status and severity, must be considered on a case-by-case basis.
Limitations
Small sample size and selection bias are the primary limitations of our study. Although we did not deny revascularization to patients strictly based on the severity of DM, it is possible that other factors leading to limb salvage or primary amputation decisions were associated with the severity of these diseases. For example, the fact that our severe DM group was younger than our non-severe DM group suggests that our decision-making valued youth as a predictor of good outcomes.
Furthermore, our primary assessment of DM control was based on SVS reporting standards and is not as specific as stratification by class of oral medication(s) or insulin regimen. In addition to this lack of specificity regarding method of DM control, the variability of HgbA1c values in our controlled and uncontrolled DM groups may have masked the detection of true differences between these groups. While increased sample sizes may enable such detection, we suspect that the extent of DM control assessed by SVS reporting standards is an insufficient proxy for DM severity. Finally, while glycosylated hemoglobin values quantified DM severity at the time of surgery, these values were not assessed in the years preceding surgery or longitudinally after surgery. Thus, pre-operative HgbA1c may not completely reflect long-term extent of glycemic control. A more comprehensive assessment of patients DM status, including medication class, insulin regimen, the duration of DM, and longitudinal HgbA1c values (both pre- and post-operative), would be greatly beneficial to our understanding of the interaction between DM and outcomes in CLTI.
Conclusion
We conducted a retrospective cohort study of patients at our LPP with CLTI and DM to evaluate the relationship between DM severity and control with survival, limb loss, wound healing, and patency. Patients with higher HgbA1c values are at greater risk of early amputation, but other outcomes were not associated with DM characteristics. While severity of DM alone should not exclude patients from revascularization, aggressive attempts at improving glycemic control in limb salvage candidates are warranted. Patients with elevated HgbA1c should receive careful education regarding their increased risk of amputation and the importance of the relationship between DM and CLTI. Future work is needed to incorporate the severity of DM into risk models of revascularization for the CLTI population.
Acknowledgments
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported in part by National Institutes of Health award R01 HL135103 [MR Stacy].
Footnotes
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Declaration of Conflicting Interests:
The Authors declare that there is no conflict of interest.
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