The impact of diabetes mellitus on the outcomes of revascularization for chronic limb-threatening ischemia in the BEST-CLI trial.

OBJECTIVE: Several observational studies have demonstrated an association between diabetes mellitus (DM) and above-ankle amputation after lower extremity revascularization (LER). However, data from prospective randomized trials is lacking. This analysis compares the outcomes of patients with and without DM enrolled in the Best Endovascular vs Best Surgical Therapy in patients with Chronic Limb-Threatening Ischemia (BEST-CLI) trial. METHODS: Baseline characteristics were compared between patients with and without DM in the BEST-CLI trial. Cox regression was used to determine the association between DM and major outcomes of major adverse limb events (MALE), reintervention, above-ankle amputation, and all-cause death. RESULTS: Among 1777 patients who underwent LER, 69.2% had DM. Compared with patients without DM, those with DM were significantly younger, less likely to be White, and more likely to be Hispanic. Patients with DM were more likely to have hypertension, hyperlipidemia, coronary artery disease, congestive heart failure, and renal disease and be on optimal medical therapy (antiplatelets and statins), whereas patients without DM were significantly more likely to be smokers and have chronic obstructive pulmonary disease. Patients with DM were significantly more likely to present with late Wound Ischemia foot Infection (WIfI) stages (3-4) (73.7% vs 45.9%; P < .001) that were driven predominantly by differences in wound and infection grade. Conversely, patients without DM had significantly lower ankle pressures and toe pressures and were significantly more likely to have WIfI ischemia grade 3 compared with patients with DM (60% vs 52.5%; P = .016). At 3 years, patients with DM exhibited higher rates of above-ankle amputation and all-cause death compared with patients without DM. Kaplan-Meier analysis demonstrated significantly higher MALE or all-cause death compared with patients without DM (3-year estimate: 53.5% vs 46.4%; P < .001). After adjusting for potential confounders, regression analysis demonstrated that DM was independently associated with increased above-ankle amputation (1.75 [1.22-2.51]), all-cause death (1.63 [1.31-2.03]), and MALE or all-cause death (1.24 [1.04-1.47]). CONCLUSIONS: Patients with DM undergoing LER for chronic limb-threatening ischemia experienced a greater incidence of MALE or all-cause death compared with patients without DM. The impact of DM seems to be mediated by more severe wounds and infections at the time of presentation, and a higher prevalence of cardiac and renal disease.

Trends in patient characteristics and mortality among Medicare patients diagnosed with peripheral artery disease.

INTRODUCTION: Peripheral artery disease (PAD) is a well-described risk factor for mortality, but few studies have examined secular trends in mortality over time for patients with PAD. We characterized trends in mortality in patients with PAD in recent years among Medicare patients. METHODS: We used Medicare claims to identify patients with a new diagnosis code for PAD between January 1, 2006 and December 31, 2018 using International Classification of Diseases (ICD) diagnosis codes. The primary outcome of interest was the 1-year all-cause age-adjusted mortality rate. Our secondary outcome was the 5-year all-cause mortality rate. Multivariable regression was used to identify factors which predict mortality at 1 year. RESULTS: We identified 4,373,644 patients with a new diagnosis code for PAD during the study period. Between 2006 and 2018, 1-year all-cause age-adjusted mortality declined from 12.6% to 9.9% (p < 0.001). One-year crude all-cause mortality also declined from 14.6% to 9.5% (p < 0.001). Similar results were observed for 5-year age-adjusted mortality rates (40.9% to 35.2%, p < 0.001). Factors associated with increased risk of death at 1 year included age ⩾ 85 years (hazard ratio [HR] 3.030; 95% CI 3.008-3.053) and congestive heart failure (HR 1.86; 95% CI 1.85-1.88). Patients who were regularly dispensed statins, ace-inhibitors, beta-blockers, antithrombotic agents, and anticoagulants all had lower mortality (range OR 0.36; CI 0.35-0.37 for statins to OR 0.60; CI 0.59-0.61 for anticoagulants; all p < 0.001). CONCLUSION: Among US Medicare patients diagnosed with PAD between 2006 and 2019, 1-year age-adjusted mortality declined by 2.7%. This decline in mortality among PAD patients occurred in the context of a younger mean age of diagnosis of PAD and improved cardiovascular prevention therapy.

Reduction of Major Amputations after Surgery versus Endovascular Intervention: The BEST-CLI Randomised Trial.

OBJECTIVE: BEST-CLI, an international randomised trial, compared an initial strategy of bypass surgery with endovascular treatment in chronic limb threatening ischaemia (CLTI). In this substudy, overall amputation rates and risk of major amputation as an initial or subsequent outcome were evaluated. METHODS: A total of 1 830 patients were randomised to receive surgical or endovascular treatment in two parallel cohorts: patients with adequate single segment great saphenous vein (SSGSV) (n = 1 434) were assigned to cohort 1; and patients without adequate SSGSV (n = 396) were assigned to cohort 2. Differences in time to first event and number of amputations were evaluated. RESULTS: In cohort 1, there were 410 (45.6%) total amputation events in the surgical group vs. 490 (54.4%) in the endovascular group (p = .001) during a mean follow up of 2.7 years. Approximately one in three patients underwent minor amputation after index revascularisation: 31.5% of the surgical group vs. 34.9% in the endovascular group (p = .17). Subsequent major amputation was required significantly less often in the surgical group compared with the endovascular group (15.0% vs. 25.6%; p = .002). The first amputation was major in 5.6% of patients in the surgical group and 6.0% in the endovascular group (p = .72). Major amputation was required in 10.3% (74/718) of patients in the surgical group and 14.9% (107/716) in the endovascular group (p = .008). In cohort 2, there were 199 amputation events in 132 patients (33.3%) during a mean follow up of 1.6 years: 95 (47.7%) in the surgical group vs. 104 (52.3%) in the endovascular group (p = .49). Major amputation was required in 15.2% (30/197) of patients in the surgical group and 14.1% (28/199) in the endovascular group (p = .74). CONCLUSION: In patients with CLTI, surgical bypass with SSGSV was more effective than endovascular treatment in preventing major amputations, mainly due to a decrease in major amputations subsequent to minor amputations.

Association between tissue loss type and amputation risk among Medicare patients with concomitant diabetes and peripheral arterial disease.

OBJECTIVE: Prior studies have described risk factors associated with amputation in patients with concomitant diabetes and peripheral arterial disease (DM/PAD). However, the association between the severity and extent of tissue loss type and amputation risk remains less well-described. We aimed to quantify the role of different tissue loss types in amputation risk among patients with DM/PAD, in the context of demographic, preventive, and socioeconomic factors. METHODS: Applying International Classification of Diseases (ICD)-9 and ICD-10 codes to Medicare claims data (2007-2019), we identified all patients with continuous fee-for-service Medicare coverage diagnosed with DM/PAD. Eight tissue loss categories were established using ICD-9 and ICD-10 diagnosis codes, ranging from lymphadenitis (least severe) to gangrene (most severe). We created a Cox proportional hazards model to quantify associations between tissue loss type and 1- and 5-year amputation risk, adjusting for age, race/ethnicity, sex, rurality, income, comorbidities, and preventive factors. Regional variation in DM/PAD rates and risk-adjusted amputation rates was examined at the hospital referral region level. RESULTS: We identified 12,257,174 patients with DM/PAD (48% male, 76% White, 10% prior myocardial infarction, 30% chronic kidney disease). Although 2.2 million patients (18%) had some form of tissue loss, 10.0 million patients (82%) did not. The 1-year crude amputation rate (major and minor) was 6.4% in patients with tissue loss, and 0.4% in patients without tissue loss. Among patients with tissue loss, the 1-year any amputation rate varied from 0.89% for patients with lymphadenitis to 26% for patients with gangrene. The 1-year amputation risk varied from two-fold for patients with lymphadenitis (adjusted hazard ratio, 1.96; 95% confidence interval, 1.43-2.69) to 29-fold for patients with gangrene (adjusted hazard ratio, 28.7; 95% confidence interval, 28.1-29.3), compared with patients without tissue loss. No other demographic variable including age, sex, race, or region incurred a hazard ratio for 1- or 5-year amputation risk higher than the least severe tissue loss category. Results were similar across minor and major amputation, and 1- and 5-year amputation outcomes. At a regional level, higher DM/PAD rates were inversely correlated with risk-adjusted 5-year amputation rates (R2 = 0.43). CONCLUSIONS: Among 12 million patients with DM/PAD, the most significant predictor of amputation was the presence and extent of tissue loss, with an association greater in effect size than any other factor studied. Tissue loss could be used in awareness campaigns as a simple marker of high-risk patients. Patients with any type of tissue loss require expedited wound care, revascularization as appropriate, and infection management to avoid amputation. Establishing systems of care to provide these interventions in regions with high amputation rates may prove beneficial for these populations.

Quality of Life in Patients With Chronic Limb-Threatening Ischemia Treated With Revascularization.

BACKGROUND: In the BEST-CLI trial (Best Endovascular Versus Best Surgical Therapy for Patients With Chronic Limb-Threatening Ischemia), a prespecified secondary objective was to assess the effects of revascularization strategy on health-related quality of life (HRQoL). METHODS: Patients with chronic limb-threatening ischemia were randomized to surgical bypass (Bypass) or endovascular intervention (Endo) in 2 parallel trials. Cohort 1 included patients with single-segment great saphenous vein; cohort 2 included those lacking suitable single-segment great saphenous vein. HRQoL was assessed over the trial duration using Vascular Quality-of-Life (VascuQoL), European Quality-of-Life-5D (EQ-5D), the Short Form-12 (SF-12) Physical Component Summary (SF-12 PCS), SF-12 Mental Component Summary (SF-12 MCS), Utility Index Score (SF-6D R2), and numeric rating scales of pain. HRQoL was summarized by cohort and compared within and between groups using mixed-model linear regression. RESULTS: A total of 1193 and 335 patients in cohorts 1 and 2 with a mean follow-up of 2.9 and 2.0 years, respectively, were analyzed. In cohort 1, HRQoL significantly improved from baseline to follow-up for both groups across all measures. For example, mean (SD) VascuQoL scores were 3.0 (1.3) and 3.0 (1.2) for Bypass and Endo at baseline and 4.7 (1.4) and 4.8 (1.5) over follow-up. There were significant group differences favoring Endo when assessed with VascuQoL (difference, -0.14 [95% CI, -0.25 to -0.02]; P=0.02), SF-12 MCS (difference, -1.03 [95% CI, -1.89 to -0.18]; P=0.02), SF-6D R2 (difference, -0.01 [95% CI, -0.02 to -0.001]; P=0.03), numeric rating scale pain at present (difference, 0.26 [95% CI, 0.03 to 0.49]; P=0.03), usual level during previous week (difference, 0.26 [95% CI, 0.04 to 0.48]; P=0.02), and worst level during previous week (difference, 0.29 [95% CI, 0.02 to 0.56]; P=0.04). There was no difference between treatment arms on the basis of EQ-5D (difference, -0.01 [95% CI, -0.03 to 0.004]; P=0.12) or SF-12 PCS (difference, -0.41 [95% CI, -1.2 to 0.37]; P=0.31). In cohort 2, HRQoL also significantly improved from baseline to the end of follow-up for both groups based on all measures, but there were no differences between Bypass and Endo on any measure. CONCLUSIONS: Among patients with chronic limb-threatening ischemia deemed eligible for either Bypass or Endo, revascularization resulted in significant and clinically meaningful improvements in HRQoL. In patients with an available single-segment great saphenous vein for bypass, but not among those without one, Endo was statistically superior on some HRQoL measures; however, these differences were below the threshold of clinically meaningful difference.

The impact of the Affordable Care Act Medicaid Expansion in Medicare beneficiaries with peripheral artery disease.

Background: In 2014, the Affordable Care Act Medicaid Expansion (ME) increased Medicaid eligibility for adults with an income level up to 138% of the federal poverty level. In this study, we examined the impact of ME on mortality and amputation in patients with peripheral artery disease (PAD). Methods: The 100% MedPAR and Part-B Carrier files from 2011 to 2018 were queried to identify all fee-for-service Medicare beneficiaries with PAD using International Classification of Diseases codes. Our primary exposure was whether a state had adopted the ME on January 1, 2014. Our primary outcomes were the change in all-cause 1-year mortality and leg amputation. We used a state-level difference-in-differences (DID) analysis to compare the rates of the primary outcomes among patients who were in states (including the District of Columbia) who adopted ME (n = 25) versus those who were in states that did not (n = 26). We performed a subanalysis stratifying by sex, race, region, and dual-eligibility status. Results: Over the 8-year period, we studied 37,743,929 patients. The average unadjusted 1-year mortality decreased from 2011 to 2018 in both non-ME (9.5% to 8.7%, p < 0.001) and ME (9.1% to 8.3%, p < 0.001) states. The average unadjusted 1-year amputation rate did not improve in either the non-ME (0.86% to 0.87%, p = 0.17) or ME (0.69% to 0.69%, p = 0.65) states. Across the entire cohort, the DID model revealed that ME did not lead to a significant change in mortality (p = 0.15) or amputation (p = 0.34). Conclusion: Medicaid Expansion was not associated with reduced mortality or leg amputation in Medicare beneficiaries with PAD.

Addressing Barriers to Entry and Retention of Women in Interventional Vascular Specialties With Proposed Solutions: A Scientific Statement From the American Heart Association.

Representation of women in interventional vascular fields (interventional cardiology, interventional radiology, and vascular surgery) lags behind that in other specialties. With women representing half of all medical school graduates, encouraging parity of women in these fields needs to start in medical school. Barriers to pursuing careers in vascular intervention include insufficient exposure during core clerkships, early mentorship, visibility of women in the field, length of training, lifestyle considerations, work culture and environment, and concerns about radiation exposure. This scientific statement highlights potential solutions for both the real and perceived barriers that women may face in pursuing careers in vascular intervention, including streamlining of training (as both interventional radiology and vascular surgery have done with a resultant increase in percentage of women trainees), standardization of institutional promotion of women in leadership, and professional and industry partnerships for the retention and advancement of women.

Challenges and Controversies in Peer Review: JACC Review Topic of the Week.

The process of peer review has been the gold standard for evaluating medical science, but significant pressures from the recent COVID-19 pandemic, new methods of communication, larger amounts of research, and an evolving publication landscape have placed significant pressures on this system. A task force convened by the American College of Cardiology identified the 5 most significant controversies associated with the current peer-review process: the effect of preprints, reviewer blinding, reviewer selection, reviewer incentivization, and publication of peer reviewer comments. Although specific solutions to these issues will vary, regardless of how scientific communication evolves, peer review must remain an essential process for ensuring scientific integrity, timely dissemination of information, and better patient care. In medicine, the peer-review process is crucial because harm can occur if poor-quality data or incorrect conclusions are published. With the dramatic increase in scientific publications and new methods of communication, high-quality peer review is more important now than ever.

Therapeutic anticoagulation after index peripheral endovascular intervention in patients with claudication.

OBJECTIVE: Antiplatelet agents are commonly used after peripheral endovascular intervention (PVI). However, the effect of full-dose anticoagulation on outcomes after PVI is not well-established. We sought to investigate whether full-dose anticoagulation after PVI is associated with adverse events. METHODS: We utilized the Vascular Quality Initiative to study patients undergoing index PVI for claudication (2010-2019), stratified by the presence or absence of an anticoagulant on discharge. The primary outcomes were 2-year patency, major adverse limb events (MALE), and mortality. We built a propensity score adjusting for comorbidities and employed inverse probability weighting to estimate the association of anticoagulation with outcomes. RESULTS: We identified 26,240 patients; 9.1% were discharged on an anticoagulant. Patients receiving any anticoagulation had a significantly higher risk of mortality (adjusted hazard ratio [aHR], 1.61; 95% confidence interval [CI], 1.35-1.92), but not MALE, or patency loss. Patients receiving a vitamin K antagonist had a significantly higher risk of patency loss (aHR, 1.32; 95% CI, 1.09-1.60), MALE (aHR, 1.33; 95% CI, 1.13-1.57), and mortality (aHR, 1.46; 95% CI, 1.27-1.69). Patients on an oral Factor Xa inhibitors had a significantly lower risk of patency loss (aHR, 0.61; 95% CI, 0.41-0.93) but increased mortality (aHR, 1.51; 95% CI, 1.19-1.92). CONCLUSIONS: Therapeutic anticoagulation after PVI is associated with higher risk of all-cause mortality. Although oral Factor Xa inhibitors are associated with decreased risk of patency loss, vitamin K antagonists are associated with higher risk of patency loss, MALE, and death. Further prospective studies are necessary to study the safety and efficacy of full-dose anticoagulation after PVI.

Long-Term Patient Outcomes After Femoropopliteal Peripheral Vascular Intervention in Patients With Intermittent Claudication.

BACKGROUND: In patients with intermittent claudication (IC), short-term amputation rates from clinical trial data following lower extremity femoropopliteal (FP) peripheral vascular intervention (PVI) are <1% with unknown longer-term rates. OBJECTIVES: The aim of this study was to identify revascularization and amputation rates following PVI in the FP segment and to assess 4-year amputation and revascularization rates after FP PVI for IC. METHODS: From 2016 to 2020, 19,324 patients undergoing FP PVI for IC were included from the PINC AI Healthcare Database and evaluated by treatment level (superficial femoral artery [SFA], popliteal artery [POP], or both). The primary outcome was index limb amputation (ILA) assessed by Kaplan-Meier estimate. The secondary outcomes were index limb major amputation and repeat revascularization. HRs were estimated using Cox proportional hazard regression. RESULTS: The 4-year index limb amputation rate following FP PVI was 4.3% (95% CI: 4.0-4.7), with a major amputation rate of 3.2% (95% CI: 2.9-3.5). After POP PVI, ILA was significantly higher than SFA alone (7.5% vs 3.4%) or both segment PVI (5.5%). In multivariate analysis, POP PVI was associated with higher ILA rates at 4 years compared with isolated SFA PVI (HR: 2.10; 95% CI: 1.52-2.91) and index limb major amputation (HR: 1.98; 95% CI: 1.32-2.95). Repeat FP revascularization rates were 15.2%; they were highest in patients undergoing both SFA and POP PVI (18.7%; P < 0.0001) compared with SFA (13.9%) and POP (17.1%) only. CONCLUSIONS: IC patients undergoing FP PVI had 4-year rates of index limb repeat revascularization of 16.7% and ILA rates of 4.3%. Further risk factors for amputation requires further investigation.

Trends of Concomitant Diabetes and Peripheral Artery Disease and Lower Extremity Amputation in US Medicare Patients, 2007 to 2019.

BACKGROUND: Previous studies demonstrate geographic and racial/ethnic variation in diagnosis and complications of diabetes and peripheral artery disease (PAD). However, recent trends for patients diagnosed with both PAD and diabetes are lacking. We assessed the period prevalence of concurrent diabetes and PAD across the United States from 2007 to 2019 and regional and racial/ethnic variation in amputations among Medicare patients. METHODS: Using Medicare claims from 2007 to 2019, we identified patients with both diabetes and PAD. We calculated period prevalence of concomitant diabetes and PAD and incident cases of diabetes and PAD for every year. Patients were followed to identify amputations, and results were stratified by race/ethnicity and hospital referral region. RESULTS: 9 410 785 patients with diabetes and PAD were identified (mean age, 72.8 [SD, 10.94] years; 58.6% women, 74.7% White, 13.2% Black, 7.3% Hispanic, 2.8% Asian/API, and 0.6% Native American). Period prevalence of diabetes and PAD was 23 per 1000 beneficiaries. We observed a 33% relative decrease in annual new diagnoses throughout the study. All racial/ethnic groups experienced a similar decline in new diagnoses. Black and Hispanic patients had on average a 50% greater rate of disease compared with White patients. One- and 5-year amputation rates remained stable at ≈1.5% and 3%, respectively. Native American, Black, and Hispanic patients were at greater risk of amputation compared with White patients at 1- and 5-year time points (5-year rate ratio range, 1.22-3.17). Across US regions, we observed differential amputation rates, with an inverse relationship between the prevalence of concomitant diabetes and PAD and overall amputation rates. CONCLUSIONS: Significant regional and racial/ethnic variation exists in the incidence of concomitant diabetes and PAD among Medicare patients. Black patients in areas with the lowest rates of PAD and diabetes are at disproportionally higher risk for amputation. Furthermore, areas with higher prevalence of PAD and diabetes have the lowest rates of amputation.

Impaired angiogenesis in diabetic critical limb ischemia is mediated by a miR-130b/INHBA signaling axis.

Patients with peripheral artery disease (PAD) and diabetes compose a high-risk population for development of critical limb ischemia (CLI) and amputation, although the underlying mechanisms remain poorly understood. Comparison of dysregulated microRNAs from diabetic patients with PAD and diabetic mice with limb ischemia revealed the conserved microRNA, miR-130b-3p. In vitro angiogenic assays demonstrated that miR-130b rapidly promoted proliferation, migration, and sprouting in endothelial cells (ECs), whereas miR-130b inhibition exerted antiangiogenic effects. Local delivery of miR-130b mimics into ischemic muscles of diabetic mice (db/db) following femoral artery ligation (FAL) promoted revascularization by increasing angiogenesis and markedly improved limb necrosis and amputation. RNA-Seq and gene set enrichment analysis from miR-130b-overexpressing ECs revealed the BMP/TGF-ß signaling pathway as one of the top dysregulated pathways. Accordingly, overlapping downregulated transcripts from RNA-Seq and miRNA prediction algorithms identified that miR-130b directly targeted and repressed the TGF-ß superfamily member inhibin-ß-A (INHBA). miR-130b overexpression or siRNA-mediated knockdown of INHBA induced IL-8 expression, a potent angiogenic chemokine. Lastly, ectopic delivery of silencer RNAs (siRNA) targeting Inhba in db/db ischemic muscles following FAL improved revascularization and limb necrosis, recapitulating the phenotype of miR-130b delivery. Taken together, a miR-130b/INHBA signaling axis may provide therapeutic targets for patients with PAD and diabetes at risk of developing CLI.

A miRNA/CXCR4 signaling axis impairs monopoiesis and angiogenesis in diabetic critical limb ischemia.

Patients with peripheral artery disease (PAD) and diabetes have the highest risk of critical limb ischemia (CLI) and amputation, yet the underlying mechanisms remain incompletely understood. MicroRNA (miRNA) sequencing of plasma from diabetic patients with or without CLI was compared to diabetic mice with acute or subacute limb ischemia to identify conserved miRNAs. miRNA-KO mice on high-fat diet were generated to explore the impact on CLI. Comparison of dysregulated miRNAs from diabetic individuals with PAD and diabetic mice with limb ischemia revealed conserved miR-181 family members. High-fat-fed, diabetic Mir181a2b2-KO mice had impaired revascularization in limbs due to abrogation of circulating Ly6Chi monocytes, with reduced accumulation in ischemic skeletal muscles. M2-like KO macrophages under diabetic conditions failed to produce proangiogenic cytokines. Single-cell transcriptomics of the bone marrow niche revealed that the reduced monocytosis in diabetic KO mice was a result of impaired hematopoiesis, with increased CXCR4 signaling in bone marrow Lineage-Sca1+Kit+ (LSK) cells. Exogenous Ly6Chi monocytes from nondiabetic KO mice rescued the impaired revascularization in ischemic limbs of diabetic KO mice. Increased Cxcr4 expression was mediated by the miR-181 target, Plac8. Taken together, our results show that MiR-181a/b is a putative mediator of diabetic CLI and contributes to changes in hematopoiesis, monocytosis, and macrophage polarization.

Association of Anticoagulation and Major Adverse Limb Events After Index Peripheral Endovascular Intervention.

Dual-antiplatelet therapy is commonly prescribed after endovascular intervention for peripheral artery disease. However, it is not known whether therapeutic anticoagulation affects outcomes after peripheral endovascular intervention. We sought to investigate whether therapeutic anticoagulation after peripheral endovascular intervention is associated with lower risk of major adverse limb events (MALEs) and all-cause mortality. We studied patients who underwent index endovascular intervention for peripheral artery disease in the Vascular Study Group of New England (2010 to 2018). The main exposure was anticoagulation at the time of discharge. Outcomes included patency loss (occlusion or target lesion reintervention), MALE (any major amputation or reintervention), and all-cause mortality. We compared outcomes between patients who received anticoagulation on discharge versus those who did not receive anticoagulation using Kaplan-Meier survival analysis and Cox regression. In the cohort of 6,809 patients, 15% were discharged on an anticoagulant (mostly warfarin). These patients had a higher prevalence of acute or chronic limb ischemia than those not receiving an anticoagulant (74% vs 47%, p < 0.001) and were less likely to receive any antiplatelet agent after peripheral endovascular intervention (5% vs 14%, p < 0.001). After risk adjustment, compared with patients not on an anticoagulant, patients receiving therapeutic anticoagulation had a higher risk of 2-year patency loss (hazard ratio [HR] 1.41, 95% confidence interval [CI] 1.05 to 1.89), MALE (HR 1.39, 95% CI 1.09 to 1.76), and all-cause mortality (HR 1.24, 95% CI 1.05 to 1.47). In conclusion, anticoagulation after peripheral endovascular intervention was associated with higher risk of adverse events, including patency loss, MALE, and all-cause mortality.

MicroRNA-375 repression of Kruppel-like factor 5 improves angiogenesis in diabetic critical limb ischemia.

Peripheral artery disease (PAD) is an occlusive disease of limb arteries. Critical limb ischemia (CLI) is an advanced form of PAD that is prognostically worse in subjects with diabetes and can result in limb loss, gangrene, and death, although the underlying signaling mechanisms that contribute to its development remain poorly understood. By comparing plasma samples from diabetic humans with PAD and mouse models of PAD, we identified miR-375 to be significantly downregulated in humans and mice during progression to CLI. Overexpression of miR-375 was pro-angiogenic in endothelial cells in vitro and induced endothelial migration, proliferation, sprouting, and vascular network formation, whereas miR-375 inhibition conferred anti-angiogenic effects. Intramuscular delivery of miR-375 improved blood flow recovery to diabetic mouse hindlimbs following femoral artery ligation (FAL) and improved neovessel growth and arteriogenesis in muscle tissues. Using RNA-sequencing and prediction algorithms, Kruppel-like factor 5 (KLF5) was identified as a direct target of miR-375 and siRNA knockdown of KLF5 phenocopied the effects of miR-375 overexpression in vitro and in vivo through regulatory changes in NF-kB signaling. Together, a miR-375-KLF5-NF-kB signaling axis figures prominently as a potential therapeutic pathway in the development CLI in diabetes.

Deriving International Classification of Diseases, 9th and 10th revision, codes for identifying and following up patients with diabetic lower extremity ulcers.

Objective: Administrative claims data offer a rich data source for clinical research. However, its application to the study of diabetic lower extremity ulceration is lacking. Our objective was to create a widely applicable framework by which investigators might derive and refine the International Classification of Diseases, 9th and 10th revision (ICD-9 and ICD-10, respectively) codes for use in identifying diabetic, lower extremity ulceration. Methods: We created a seven-step process to derive and refine the ICD-9 and ICD-10 coding lists to identify diabetic lower extremity ulcers. This process begins by defining the research question and the initial identification of a list of ICD-9 and ICD-10 codes to define the exposures or outcomes of interest. These codes are then applied to claims data, and the rates of clinical events are examined for consistency with prior research and changes across the ICD-9 to ICD-10 transition. The ICD-9 and ICD-10 codes are then cross referenced with each other to further refine the lists. Results: Using this method, we started with 8 ICD-9 and 43 ICD-10 codes used to identify lower extremity ulcers in patients with known diabetes and peripheral arterial disease and examined the association of ulceration with lower extremity amputation. After refinement, we had 45 ICD-9 codes and 304 ICD-10 codes. We then grouped the codes into eight clinical exposure groups and examined the rates of amputation as a rudimentary test of validity. We found that the rate of lower extremity amputation correlated with the severity of lower extremity ulceration. Conclusions: We identified 45 ICD-9 and 304 ICD-10 ulcer codes, which identified patients at risk of amputation from diabetes and peripheral artery disease. Although further validation at the medical record level is required, these codes can be used for claims-based risk stratification for long-term outcomes assessment in the treatment of patients at risk of limb loss.

Using a cohort study of diabetes and peripheral artery disease to compare logistic regression and machine learning via random forest modeling.

BACKGROUND: This study illustrates the use of logistic regression and machine learning methods, specifically random forest models, in health services research by analyzing outcomes for a cohort of patients with concomitant peripheral artery disease and diabetes mellitus. METHODS: Cohort study using fee-for-service Medicare beneficiaries in 2015 who were newly diagnosed with peripheral artery disease and diabetes mellitus. Exposure variables include whether patients received preventive measures in the 6 months following their index date: HbA1c test, foot exam, or vascular imaging study. Outcomes include any reintervention, lower extremity amputation, and death. We fit both logistic regression models as well as random forest models. RESULTS: There were 88,898 fee-for-service Medicare beneficiaries diagnosed with peripheral artery disease and diabetes mellitus in our cohort. The rate of preventative treatments in the first six months following diagnosis were 52% (n = 45,971) with foot exams, 43% (n = 38,393) had vascular imaging, and 50% (n = 44,181) had an HbA1c test. The directionality of the influence for all covariates considered matched those results found with the random forest and logistic regression models. The most predictive covariate in each approach differs as determined by the t-statistics from logistic regression and variable importance (VI) in the random forest model. For amputation we see age 85 + (t = 53.17) urban-residing (VI = 83.42), and for death (t = 65.84, VI = 88.76) and reintervention (t = 34.40, VI = 81.22) both models indicate age is most predictive. CONCLUSIONS: The use of random forest models to analyze data and provide predictions for patients holds great potential in identifying modifiable patient-level and health-system factors and cohorts for increased surveillance and intervention to improve outcomes for patients. Random forests are incredibly high performing models with difficult interpretation most ideally suited for times when accurate prediction is most desirable and can be used in tandem with more common approaches to provide a more thorough analysis of observational data.

Surgery or Endovascular Therapy for Chronic Limb-Threatening Ischemia.

BACKGROUND: Patients with chronic limb-threatening ischemia (CLTI) require revascularization to improve limb perfusion and thereby limit the risk of amputation. It is uncertain whether an initial strategy of endovascular therapy or surgical revascularization for CLTI is superior for improving limb outcomes. METHODS: In this international, randomized trial, we enrolled 1830 patients with CLTI and infrainguinal peripheral artery disease in two parallel-cohort trials. Patients who had a single segment of great saphenous vein that could be used for surgery were assigned to cohort 1. Patients who needed an alternative bypass conduit were assigned to cohort 2. The primary outcome was a composite of a major adverse limb event - which was defined as amputation above the ankle or a major limb reintervention (a new bypass graft or graft revision, thrombectomy, or thrombolysis) - or death from any cause. RESULTS: In cohort 1, after a median follow-up of 2.7 years, a primary-outcome event occurred in 302 of 709 patients (42.6%) in the surgical group and in 408 of 711 patients (57.4%) in the endovascular group (hazard ratio, 0.68; 95% confidence interval [CI], 0.59 to 0.79; P<0.001). In cohort 2, a primary-outcome event occurred in 83 of 194 patients (42.8%) in the surgical group and in 95 of 199 patients (47.7%) in the endovascular group (hazard ratio, 0.79; 95% CI, 0.58 to 1.06; P = 0.12) after a median follow-up of 1.6 years. The incidence of adverse events was similar in the two groups in the two cohorts. CONCLUSIONS: Among patients with CLTI who had an adequate great saphenous vein for surgical revascularization (cohort 1), the incidence of a major adverse limb event or death was significantly lower in the surgical group than in the endovascular group. Among the patients who lacked an adequate saphenous vein conduit (cohort 2), the outcomes in the two groups were similar. (Funded by the National Heart, Lung, and Blood Institute; BEST-CLI ClinicalTrials.gov number, NCT02060630.).

Association of Sex and Race With Incident Peripheral Artery Disease Among Veterans With Normal Ankle-Brachial Indices.

Importance: Reported risk of incident peripheral artery disease (PAD) by sex and race varies significantly and has not been reported in national cohorts among individuals free of baseline PAD. Objective: To evaluate the association of sex and race, as well as prevalent cardiovascular risk factors, with limb outcomes in a national cohort of people with normal baseline ankle-brachial indices (ABIs). Design, setting, and participants: This cohort study was conducted using data from participants in the Veterans Affairs Birth Cohort Study (born 1945-1965), with follow-up data between January 1, 2000, and December 31, 2016. Baseline demographics were collected from 77 041 participants receiving care from the Veterans Health Administration with baseline ABIs of 0.90 to 1.40 and no history of PAD. Data were analyzed from October 2019 through September 2022. Exposures: Sex, race, diabetes, and smoking status. Main Outcomes and Measures: Incident PAD, defined as subsequent ABI less than 0.90, surgical or percutaneous revascularization, or nontraumatic amputation. Results: Of 77 041 participants with normal ABIs (73 822 [95.8%] men; mean [SD] age, 60.2 [5.9] years; 13 080 Black [18.2%] and 54 377 White [75.6%] among 71 911 participants with race and ethnicity data), there were 6692 incident PAD events over a median [IQR] of 3.9 [1.7-6.9] years. Incidence rates were lower for women than men (incidence rates [IRs] per 1000 person-years, 7.4 incidents [95% CI, 6.2-8.8 incidents] vs 19.2 incidents [95% CI, 18.7-19.6 incidents]), with a lower risk of incident PAD (adjusted hazard ratio [aHR], 0.49 [95% CI, 0.41-0.59]). IRs per 1000 person-years of incident PAD were similar for Black and White participants (18.9 incidents [95% CI, 17.9-20.1 incidents] vs 18.8 incidents [95% CI, 18.3-19.4]). Compared with White participants, Black participants had increased risk of total PAD (aHR, 1.09 [95% CI, 1.02-1.16]) and nontraumatic amputation (aHR, 1.20 [95% CI, 1.06-1.36]) but not surgical or percutaneous revascularization (aHR, 1.10 [95% CI, 0.98-1.23]) or subsequent ABI less than 0.90 (aHR, 1.04 [95% CI, 0.95-1.13]). Diabetes (aHR, 1.62 [95% CI, 1.53-1.72]) and smoking (eg, current vs never: aHR, 1.76 [95% CI, 1.64-1.89]) were associated with incident PAD. Incident PAD was rare among individuals without a history of smoking or diabetes (eg, among 632 women: IR per 1000 people-years, 2.1 incidents [95% CI, 1.0-4.5 incidents]) despite an otherwise-high-risk cardiovascular profile (eg, 527 women [83.4%] with hypertension). Conclusions and Relevance: This study found that the risk of PAD was approximately 50% lower in women than men and less than 10% higher for Black vs White participants, while the risk of nontraumatic amputation was 20% higher among Black compared with White participants.