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Chronic limb-threatening ischemia could benefit from growth hormone therapy for wound healing and limb salvage.

ABSTRACT: Revascularization for chronic limb-threatening ischemia (CLTI) is necessary to alleviate symptoms and wound healing. When it fails or is not possible, there are few alternatives to avoid limb amputation in these patients. Although experimental studies with stem cells and growth factors have shown promise, clinical trials have demonstrated inconsistent results because CLTI patients generally need arteriogenesis rather than angiogenesis. Moreover, in addition to the perfusion of the limb, there is the need to improve the neuropathic response for wound healing, especially in diabetic patients. Growth hormone (GH) is a pleiotropic hormone capable of boosting the aforementioned processes and adds special benefits for the redox balance. This hormone has the potential to mitigate symptoms in ischemic patients with no other options and improves the cardiovascular complications associated with the disease. Here, we discuss the pros and cons of using GH in such patients, focus on its effects on peripheral arteries, and analyze the possible benefits of treating CLTI with this hormone.

SUBMITTER: Caicedo D

PROVIDER: S-EPMC5772430 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveThe Society for Vascular Surgery Wound, Ischemia, and foot Infection (WIfI) classification system was developed to stratify the risk of 1-year major amputation. Recently, the WIfI scores were used to define the estimated revascularization benefit quartiles ranging from high benefit (Q1) to questionable benefit (Q4). The aim of our study was to evaluate the revascularization benefit quartiles in a cohort of diabetic patients presenting with chronic limb-threatening ischemia (CLTI).MethodsAll diabetic patients presenting to our multidisciplinary diabetic foot and wound clinic (June 2012 to May 2020) who underwent lower extremity revascularization for CLTI were included. The affected limbs were graded using the WIfI system and assigned to an estimated benefit of revascularization quartile as previously published. One-year major amputation, complete foot healing, secondary patency, and amputation-free survival were calculated among the quartiles using Kaplan-Meier curve analyses and compared using Cox proportional hazards models.ResultsOverall, 136 diabetic patients underwent revascularization of 187 limbs (mean age, 64.9 ± 11.2 years; 63.2% male; 58.8% black). The limbs were revascularized using an endovascular approach for 66.8% and open surgery for 33.2%. Of the 187 limbs, 27.3% had a high estimated benefit of revascularization (Q1), 31.6% had a moderate estimate benefit of revascularization (Q2), 20.3% had a low estimated benefit of revascularization (Q3), and 20.9% had a questionable benefit of revascularization (Q4). The estimated 1-year major amputation rates were 7.2% ± 4.1% for Q1, 3.8% ± 2.6% for Q2, 7.0% ± 4.8% for Q3, and 25.7% ± 7.5% for Q4 (P = .006). The estimated 1-year foot healing rates were 87.3% ± 5.7% for Q1, 84.8% ± 5.6% for Q2, 83.8% ± 7.4% for Q3, and 68.2% ± 9.1% for Q4 (P = .06). The overall secondary patency (P = .23) and amputation-free survival (P = .33) did not significantly differ among the groups. Using Cox proportional hazard modeling, the Q4 group had a significantly greater risk of major amputation compared with Q1 (hazard ratio, 4.26; 95% confidence interval, 1.15-15.70). Of the 14 limbs requiring major amputation, 9 (56.3%) had a patent revascularization at the time of amputation, including one of three limbs in Q1, two of two limbs in Q2, no limb in Q3, and six of nine limbs in Q4.ConclusionsThe questionable estimated revascularization benefit quartile using the WIfI classification system is significantly associated with 1-year major amputation in diabetic patients presenting with CLTI. Limbs with a questionable benefit of revascularization (Q4) will frequently require major amputation despite a patent revascularization, suggesting that the wound size and infection burden are the driving factors behind the elevated risk of major amputation in this group. Our findings support the previously described use of the WIfI classification system to predict revascularization benefit among diabetic patients with CLTI.

Project description:OBJECTIVE:The beneficial effect of renin-angiotensin system (RAS) inhibitors has been well-established in patients with cardiovascular disease; however, their effectiveness in patients with chronic limb-threatening ischemia (CLTI), a selected disease-burdened population, is largely unknown. The purpose of this study was to evaluate long-term outcomes of RAS inhibitor use in patients with CLTI undergoing a vascular intervention. METHODS:For this study, all patients with CLTI undergoing a first-time revascularization (bypass or endovascular) were analyzed at our institution between 2005 and 2014. Patients discharged on an RAS inhibitor (angiotensin-converting enzyme inhibitor or angiotensin receptor blocker) were compared with those not on an RAS inhibitor. The inverse probability of treatment weighting with additional regression analyses were used to determine the long-term risk of mortality and major adverse events. A sensitivity analysis was performed to assess the dose-related therapeutic response of RAS inhibitors (low-dose vs high-dose therapy). RESULTS:Between 2005 and 2014, 1303 limbs from 1161 patients were identified. Of these patients, 52% were discharged on an RAS inhibitor, with 67% discharged on a high-dose therapy and 33% on a low-dose therapy. Patients discharged on an RAS inhibitor suffered more frequently from diabetes, hypertension, and myocardial infarction, whereas those not on an RAS inhibitor had more chronic kidney disease (all P < .05). There was no difference in the proportion of patients presenting with tissue loss. After adjustment for these and other baseline covariates, RAS inhibitor use was associated with less late mortality (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.65-0.94). Discharge on a high-dose RAS inhibitor was associated with lower mortality (HR, 0.70; 95% CI, 0.57-0.86), whereas a low-dose RAS inhibitor was not associated with less mortality (HR, 0.95; 95% CI, 0.73-1.24) compared with patients not prescribed an RAS inhibitor. This association remained significant when comparing high-dose with low-dose therapy (HR, 0.74; 95% CI, 0.55-0.98). No associations were found between RAS inhibitor use and major adverse limb event (HR, 0.95; 95% CI, 0.73-1.22), major amputation (HR, 0.82; 95% CI, 0.57-1.18), or reintervention (HR, 1.05; 95% CI, 0.85-1.31). These point estimates were not different for those on angiotensin-converting enzyme inhibitors vs angiotensin receptor blockers, nor were they affected by the type of revascularization. CONCLUSIONS:Patients with CLTI prescribed an RAS inhibitor at discharge demonstrated significantly less long-term mortality, whereas limb events were unaffected. These data indicate that, in these heavily burdened patients, the benefit is restricted to those on a high dose, which underscores the importance of attaining these doses.

Project description:Chronic limb-threatening ischemia (CLTI) is associated with mortality, amputation, and impaired quality of life. These Global Vascular Guidelines (GVG) are focused on definition, evaluation, and management of CLTI with the goals of improving evidence-based care and highlighting critical research needs. The term CLTI is preferred over critical limb ischemia, as the latter implies threshold values of impaired perfusion rather than a continuum. CLTI is a clinical syndrome defined by the presence of peripheral artery disease (PAD) in combination with rest pain, gangrene, or a lower limb ulceration >2 weeks duration. Venous, traumatic, embolic, and nonatherosclerotic etiologies are excluded. All patients with suspected CLTI should be referred urgently to a vascular specialist. Accurately staging the severity of limb threat is fundamental, and the Society for Vascular Surgery Threatened Limb Classification system, based on grading of Wounds, Ischemia, and foot Infection (WIfI) is endorsed. Objective hemodynamic testing, including toe pressures as the preferred measure, is required to assess CLTI. Evidence-based revascularization (EBR) hinges on three independent axes: Patient risk, Limb severity, and ANatomic complexity (PLAN). Average-risk and high-risk patients are defined by estimated procedural and 2-year all-cause mortality. The GVG proposes a new Global Anatomic Staging System (GLASS), which involves defining a preferred target artery path (TAP) and then estimating limb-based patency (LBP), resulting in three stages of complexity for intervention. The optimal revascularization strategy is also influenced by the availability of autogenous vein for open bypass surgery. Recommendations for EBR are based on best available data, pending level 1 evidence from ongoing trials. Vein bypass may be preferred for average-risk patients with advanced limb threat and high complexity disease, while those with less complex anatomy, intermediate severity limb threat, or high patient risk may be favored for endovascular intervention. All patients with CLTI should be afforded best medical therapy including the use of antithrombotic, lipid-lowering, antihypertensive, and glycemic control agents, as well as counseling on smoking cessation, diet, exercise, and preventive foot care. Following EBR, long-term limb surveillance is advised. The effectiveness of nonrevascularization therapies (eg, spinal stimulation, pneumatic compression, prostanoids, and hyperbaric oxygen) has not been established. Regenerative medicine approaches (eg, cell, gene therapies) for CLTI should be restricted to rigorously conducted randomizsed clinical trials. The GVG promotes standardization of study designs and end points for clinical trials in CLTI. The importance of multidisciplinary teams and centers of excellence for amputation prevention is stressed as a key health system initiative.

Project description:Guideline summaryChronic limb-threatening ischemia (CLTI) is associated with mortality, amputation, and impaired quality of life. These Global Vascular Guidelines (GVG) are focused on definition, evaluation, and management of CLTI with the goals of improving evidence-based care and highlighting critical research needs. The term CLTI is preferred over critical limb ischemia, as the latter implies threshold values of impaired perfusion rather than a continuum. CLTI is a clinical syndrome defined by the presence of peripheral artery disease (PAD) in combination with rest pain, gangrene, or a lower limb ulceration >2 weeks duration. Venous, traumatic, embolic, and nonatherosclerotic etiologies are excluded. All patients with suspected CLTI should be referred urgently to a vascular specialist. Accurately staging the severity of limb threat is fundamental, and the Society for Vascular Surgery Threatened Limb Classification system, based on grading of Wounds, Ischemia, and foot Infection (WIfI) is endorsed. Objective hemodynamic testing, including toe pressures as the preferred measure, is required to assess CLTI. Evidence-based revascularization (EBR) hinges on three independent axes: Patient risk, Limb severity, and ANatomic complexity (PLAN). Average-risk and high-risk patients are defined by estimated procedural and 2-year all-cause mortality. The GVG proposes a new Global Anatomic Staging System (GLASS), which involves defining a preferred target artery path (TAP) and then estimating limb-based patency (LBP), resulting in three stages of complexity for intervention. The optimal revascularization strategy is also influenced by the availability of autogenous vein for open bypass surgery. Recommendations for EBR are based on best available data, pending level 1 evidence from ongoing trials. Vein bypass may be preferred for average-risk patients with advanced limb threat and high complexity disease, while those with less complex anatomy, intermediate severity limb threat, or high patient risk may be favored for endovascular intervention. All patients with CLTI should be afforded best medical therapy including the use of antithrombotic, lipid-lowering, antihypertensive, and glycemic control agents, as well as counseling on smoking cessation, diet, exercise, and preventive foot care. Following EBR, long-term limb surveillance is advised. The effectiveness of nonrevascularization therapies (eg, spinal stimulation, pneumatic compression, prostanoids, and hyperbaric oxygen) has not been established. Regenerative medicine approaches (eg, cell, gene therapies) for CLTI should be restricted to rigorously conducted randomizsed clinical trials. The GVG promotes standardization of study designs and end points for clinical trials in CLTI. The importance of multidisciplinary teams and centers of excellence for amputation prevention is stressed as a key health system initiative.

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Chronic limb-threatening ischemia could benefit from growth hormone therapy for wound healing and limb salvage.

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