The association of comorbid depression with mortality and amputation risk in patients with chronic limb-threatening ischemia.

OBJECTIVE: There is increasing evidence that depression is a risk factor for worse outcomes in patients with peripheral artery disease. The association of depression in patients with chronic limb-threatening ischemia (CLTI) is not well described, nor is the impact of medical treatment for depression in this patient population. The objective of this study was to investigate the prevalence of depression in patients with CLTI, its association on major amputation and all-cause mortality, and whether medical antidepressant treatment is associated with improvement in these outcomes in patients with depression. METHODS: A retrospective review of all adult patients (≥18 years old) diagnosed with CLTI from January 1, 2007, to December 31, 2018, at a single academic medical center was performed. Collected data included patient demographics, comorbidities, and diagnosis of depression within 6 months of initial CLTI diagnosis. We also collected data on use of antidepressant medications. Outcomes evaluated were need for major lower extremity amputation and all-cause mortality. Multivariable logistic regression models estimated the adjusted effects of comorbid depression and antidepressant medication use on major amputation and all-cause mortality. Kaplan-Meier survival curves illustrated the probabilities of survival and limb salvage over time, stratified by diagnosis of comorbid depression. Multivariable Cox proportional hazards models estimated the adjusted effects of comorbid depression on time to major amputation and all-cause mortality, and the adjusted effect of antidepressant treatment on time to all-cause mortality. RESULTS: A total of 2987 patients with CLTI were identified. Mean age was 68.6 years (standard deviation, 12.9 years); 56.5% were male, and 43.5% were female. Comorbid depression within 6 months of CLTI diagnosis was present in 7.1% of the cohort (212 patients). In multivariable analysis, comorbid depression was associated with a 68% increase in the odds of major amputation (adjusted odds ratio [aOR], 1.68; 95% confidence interval [CI], 1.19-2.37; P < .01), a 164% increase in the odds of all-cause mortality among patients not taking antidepressants (aOR, 2.64; 95% CI, 1.31-5.32; P = .03), and only a 6% increase in the odds of all-cause mortality among patients taking antidepressants (aOR, 1.06; 95% CI, 0.72-1.55; P = .99). The effect of comorbid depression on mortality varied significantly by whether or not the patient was taking an antidepressant medication (P = .02). CONCLUSIONS: Comorbid depression in the patient population with CLTI is associated with a worse prognosis for major lower extremity amputation overall, and a worse prognosis for all-cause mortality among patients not taking an antidepressant. Furthermore, antidepressant treatment in the presence of comorbid depression in this patient population is associated with an improvement in the odds of all-cause mortality, illustrating the potential importance of medical management of depression.

Clinical outcomes in patients with critical limb-threatening ischemia and infected ulcers following endovascular therapy are pathogen dependent: A single-center experience from 2012 to 2021.

BACKGROUND: Patients with critical limb-threatening ischemia (CLTI) and infected leg ulcers are at risk of amputation and postinterventional sepsis. METHODS: This retrospective, single-center study included patients with CLTI and infected leg ulcers who underwent endovascular treatment (EVT) between 2012 and 2021. RESULTS: The study included 712 patients, 286 (40.2%) of whom underwent amputation (minor, n = 212; major, n = 74). Gram-negative bacteria (GNB) were significantly more prevalent in amputees (36.4% vs 30.9%, p < 0.05). Patients with gram-positive bacteria (GPB) had a 4-year freedom from any amputation rate of 72% (95% CI 64-81%) compared to 52% (95% CI 42-66%) in patients with GNB identification (p < 0.05). Cox proportional regression analysis showed that GNB, male sex, mean Wound, Ischemia, and foot Infection (WIfI) score, diabetes mellitus, and end-stage renal disease were independently and positively associated with amputation (p < 0.05). The mean WIfI score and end-stage renal disease were independently and positively associated with death from any cause (p < 0.05). Staphylococcus aureus or GNB, end-stage renal disease, and diabetes mellitus were independent risk factors for sepsis after EVT (p < 0.05). Inpatient-administered antibiotic regimes had significantly higher microbiological activity in cases of GPB identification compared to GNB identification (28% vs 9%, p < 0.05). CONCLUSION: Although the isolation of both GNB and S. aureus is a risk factor for sepsis following EVT, the isolation of GNB is independently associated with higher rates of amputation, demonstrating the importance of identifying pathogens to recognize patients at high risk.

Five-year outcomes of the GORE VIABAHN Endoprosthesis for the treatment of complex femoropopliteal lesions from a Japanese postmarket surveillance study.

Introduction: The safety and effectiveness of the GORE VIABAHN Endoprosthesis for treatment of symptomatic patients with peripheral artery disease (PAD) and complex femoropopliteal (FP) lesions was assessed in a real-world Japanese practice setting. Methods: A prospective, multicenter, postmarket surveillance study was conducted from 2016 to 2017 at 64 sites in Japan. Symptomatic patients with PAD and FP lesions ⩾ 10 cm and reference vessel diameters ranging from 4.0 to 7.5 mm were eligible for enrollment. Outcome measures evaluated at 5 years were primary patency (PP), primary-assisted patency (PAP), secondary patency (SP), freedom from target lesion revascularization (fTLR), occurrence of device- or procedure-related serious adverse events (SAEs), and stent fractures. Results: A total of 321 patients were enrolled and were a mean age of 73.9 ± 8.7 years; 77.3% were men and 26.5% had chronic limb-threatening ischemia (CLTI). The mean lesion length was 23.6 ± 6.6 cm and the frequency with TASC II C/D lesions and chronic total occlusions was 86.6% and 70.4%, respectively. The Kaplan-Meier estimated PP, PAP, SP, and fTLR at 5 years was 62.4%, 74.1%, 82.3%, and 75.9%, respectively. The mean ankle-brachial index was 0.92 ± 0.15 and the mean improvement in Rutherford class was 2.3 ± 1.4, which was maintained through 5 years. The rate of cumulative device- or procedure-related SAEs through 5 years was 19.9% with only 9.3% of those occurring after the first year. No stent fractures were observed through 5 years by x-ray evaluation. Conclusion: The 5-year safety and efficacy outcomes of the endoprosthesis were clinically acceptable for treating complex FP lesions in a real-world cohort of Japanese patients with PAD. (ClinicalTrials.gov Identifier: NCT04706273).

Accuracy of maximal acceleration time of pedal arteries to diagnose critical limb-threatening ischemia.

INTRODUCTION: Maximal acceleration time of distal arteries of the foot (ATmax) is correlated to ankle-brachial index (ABI) and toe-brachial index (TBI), and seems very promising in diagnosing severe peripheral artery disease (PAD) and especially critical limb-threatening ischemia (CLTI). Our goal was to confirm the cut-off value of 215 ms to predict a toe pressure (TP) ⩽ 30 mmHg. METHODS: A 4-month retrospective study was conducted on patients addressed for suspicion of PAD. Demographic data, ABI, TBI, and Doppler ultrasound scanning parameters of the dorsal pedis and lateral plantar arteries (DPA and LPA) were recorded. RESULTS: A total of 137 patients with 258 lower limbs were included. ATmax was highly correlated to TBI (r = -0.89, p < 0.001). With the cut-off value of 215 ms, ATmax was effective to diagnose TP ⩽ 30 mmHg with a sensitivity of 93% [95% CI 77-99], a specificity of 96% [95% CI 92-98], a positive predictive value of 73% [95% CI 56-86], a negative predictive value of 99% [95% CI 97-100], and an area under the receiver operating characteristics curve of 0.99 [95% CI 0.98-1.00]. ATmax also showed promising results to rule out PAD in healthy patients. CONCLUSION: ATmax is a reliable diagnostic tool to diagnose low TP and could be a new easily performed hemodynamic criterion for diagnosis of CLTI.

Perceptions of patients with wounds due to chronic limb-threatening ischemia.

Patients with chronic limb-threatening ischemia (CLTI) face numerous barriers to caring for lower extremity wounds. We explored the perceptions of CLTI patients to their wound/management and sought to determine attitudes towards their vascular provider as well as willingness for management through telemedicine. Patients admitted to hospital for treatment of Rutherford Grade 5 and 6 CLTI were asked complete a wound evaluation survey and took part in a semi-structured interview. Semi-structured interviews were recorded, transcribed, and analyzed using an inductive coding strategy. Codes were grouped for thematic analysis and aggregated into assertions. Eleven patients with a mean age of 60 years (35-79 years) were interviewed. All patients had peripheral artery disease (PAD) and eight patients had diabetes as well. Three overarching themes were identified. First, patients appear to have limited coping mechanisms and are overwhelmed by the care of their wounds. Second, in this cohort of patients, many had become passive observers of their care as demonstrated by a limited understanding of their disease processes and detachment from wound management. The third theme was how strong the desire to do everything to prevent limb loss was, but patients acknowledged this is hard to translate into real life with limited resources. Patients with CLTI have concerns that vascular providers must recognize and address to build strong patient-provider relationships and increase activation for management of their wounds and other medical conditions. Patients who have access to technology and with guidance may be able to understand getting care through remote medicine.

Role of toll-like receptor 4 in skeletal muscle damage in chronic limb-threatening ischemia.

Objective: Toll-like receptors (TLRs) are key pattern recognition receptors in the innate immune system. In particular, the TLR4-mediated immune response has been implicated in ischemia-induced tissue injury. Mounting evidence supports a detrimental role of the innate immune system in the pathophysiology of skeletal muscle damage in patients with chronic limb-threatening ischemia (CLTI), in whom patient-oriented functional outcomes are poor. The overall aim of this study was to investigate the potential role of TLR4 in skeletal muscle dysfunction and damage in CLTI. Methods: The role of TLR4 in ischemic muscle was investigated by (1) studying TLR4 expression and distribution in human gastrocnemius muscle biopsies, (2) evaluating the functional consequences of TLR4 inhibition in myotubes derived from human muscle biopsies, and (3) assessing the therapeutic potential of modulating TLR4 signaling in ischemic muscle in a mouse hindlimb ischemia model. Results: TLR4 was found to be expressed in human muscle biopsies, with significant upregulation in samples from patients with CLTI. In vitro studies using cultured human myotubes demonstrated upregulation of TLR4 in ischemia, with activation of the downstream signaling pathway. Inhibition of TLR4 before ischemia was associated with reduced ischemia-induced apoptosis. Upregulation of TLR4 also occurred in ischemia in vivo and TLR4 inhibition was associated with decreased inflammatory cell infiltration and diminished apoptosis in the ischemic limb. Conclusions: TLR4 is upregulated and activated in ischemic skeletal muscle in patients with CLTI. Modulating TLR4 signaling in vitro and in vivo was associated with attenuation of ischemia-induced skeletal muscle damage. This strategy could be explored further for potential clinical application.

Endovascular Revascularization and Outcomes of Critical Limb-Threatening Ischemia in Trinidad and Tobago: The EVENT Pilot Study-Challenges in a Limited-Resource, Caribbean Setting.

INTRODUCTION: This retrospective study investigated major adverse limb events (MALE) and mortality outcomes in critical limb-threatening ischemia (CLTI) patients with tissue loss after an endovascular revascularization-first (EVR-1st) strategy. METHODS: MALE and mortality were assessed in 157 consecutive patients with CLTI and tissue loss from June 2019 to June 2022 at the Eric Williams Medical Sciences Complex, Trinidad and Tobago. RESULTS: 157 patients underwent the EVR-1st strategy, of whom 20 were pivoted to immediate surgical revascularization (SR). Of the remaining 137 patients, successful EVR was achieved in 112, giving a procedural success of 82% and an all-comer overall success of 71%. The mortality and MALE rates were 2.7% and 8.9% at 2 years, respectively. Males and patients with previous major amputations were at significantly higher risk for MALE (p values of 0.016 and 0.018, respectively). There was a statistically significant difference in successful EVR for both Rutherford-Baker (RB) 5 (minor) and RB 6 (major) classifications: 63 (56%) vs. 5 (20%) and 49 (44%) vs. 20 (80%), both with a p value of 0.01. There were no differences in successful EVR amongst Wound, Ischemia, Foot Infection (WIfI) clinical stages. There were no differences in successful EVR amongst the Trans-Atlantic Inter-Society Consensus (TASC II) classifications. CONCLUSIONS: This study may prove clinically informative and applicable for an EVR-1st management strategy for high-risk patients with CLTI in a limited-resource, Caribbean setting. TRIAL REGISTRATION NUMBER: NCT05547022 (retrospectively registered).