Peripheral Artery Disease Status Research Articles

Prognostic impact of peripheral artery disease in patients with and without high bleeding risk undergoing percutaneous coronary intervention.

Peripheral artery disease (PAD) is associated with worse outcomes after percutaneous coronary intervention (PCI). The aim of this study was to assess the prognostic impact of PAD according to high bleeding risk (HBR) status. Consecutive patients undergoing PCI with drug-eluting stent implantation at a tertiary-care center (Mount Sinai Hospital) between 2012 and 2019 were stratified according to HBR and PAD status. The primary outcome was major adverse cardiac events (MACE), a composite of all-cause death, myocardial infarction (MI), and stroke 1 year after PCI. Secondary outcomes included major bleeding. Out of 16,750 patients, 43% were HBR and 57% were no-HBR. Within the two groups, PAD patients were 14% and 6%, respectively, and were more likely to have comorbidities and to undergo complex PCI than no-PAD patients. Within the HBR group, PAD was associated with an increased risk of MACE (11.4% vs. 7.3%, hazard ratio [HR]: 1.59, 95% confidence interval [CI]: 1.27-1.99, p < 0.001) and a numerical nonsignificant increase of major bleeding (8.5% vs. 6.9%, HR: 1.25, 95% CI: 0.98-1.59, p = 0.066) as compared with no-PAD. Among no-HBR patients, rates of MACE and major bleeding were numerically but not significantly higher in the PAD group. After multivariable adjustment, PAD was no longer a predictor of adverse outcomes, irrespective of HBR status. At 1-year after PCI, PAD was associated with increased 1-year risks of MACE in HBR patients. After adjustment for cardiovascular risk factors and comorbidities, the effect of PAD on adverse events was largely attenuated.

Angiogenesis-related proteins as biomarkers for peripheral artery disease

BackgroundAngiogenesis plays an important role in peripheral artery disease (PAD) and angiogenesis-related proteins may act as prognostic biomarkers. This study assesses the potential for angiogenesis-related proteins to predict adverse events associated with PAD. MethodsThis was a case-control study. Patients with PAD (n = 250) and without PAD (n = 125) provided blood samples and were followed prospectively for three years. Concentrations of 17 angiogenesis-related proteins were measured in plasma. The incidence of major adverse limb event (MALE), defined as a composite of major amputation or vascular intervention, was the primary outcome. Worsening PAD status, defined as a drop in ankle brachial index ≥ 0.15, was the secondary outcome. Multivariable regression adjusted for baseline characteristics was conducted to determine the prognostication value of angiogenesis-related proteins in predicting MALE. FindingsRelative to patients without PAD, 8 proteins related to angiogenesis were expressed differentially in PAD patients. Worsening PAD status and MALE were observed in 52 (14%) and 83 (22%) patients, respectively. Hepatocyte growth factor (HGF) was the most reliable predictor of MALE (adjusted HR 0.79, 95% CI 0.15–0.86). Compared to individuals with high HGF, patients with low HGF had a decreased three-year freedom from MALE [66% vs 88%, p = 0.001], major amputation [93% vs 98%, p = 0.023], vascular intervention [68% vs 88%, p = 0.001], and worsening PAD status [81% vs 91%, p = 0.006]. InterpretationMeasuring plasma levels of HGF in individuals with PAD can assist in identifying patients at elevated risk of adverse events related to PAD who may benefit from additional evaluation or treatment.

Associations of Cardiac Biomarkers With Peripheral Artery Disease and Peripheral Neuropathy in US Adults Without Prevalent Cardiovascular Disease.

NT-proBNP (N-terminal pro-B-type natriuretic peptide), high-sensitivity cardiac troponin T (hs-troponin T), and high-sensitivity cardiac troponin I (hs-troponin I) are increasingly being recommended for risk stratification for a variety of cardiovascular outcomes. The aims of our study were to establish the prevalence and associations of elevated NT-proBNP, hs-troponin T, and hs-troponin I with lower extremity disease, including peripheral artery disease (PAD) and peripheral neuropathy (PN), in the US general adult population without known cardiovascular disease. We also assessed whether the combination of PAD or PN and elevated cardiac biomarkers was associated with an increased risk of all-cause and cardiovascular mortality. We conducted a cross-sectional analysis of the associations of NT-proBNP, hs-troponin T, and hs-troponin I with PAD (based on ankle-brachial index <0.90) and PN (diagnosed by monofilament testing) in adult participants aged ≥40 years of age without prevalent cardiovascular disease in NHANES (National Health and Nutrition Examination Survey) 1999 to 2004. We calculated the prevalence of elevated cardiac biomarkers among adults with PAD and PN and used multivariable logistic regression to assess the associations of each cardiac biomarker, modeled using clinical cut points, with PAD and PN separately. We used multivariable Cox proportional hazards models to assess the adjusted associations of cross categories of clinical categories of each cardiac biomarker and PAD or PN with all-cause and cardiovascular mortality. In US adults aged ≥40 years, the prevalence (±SE) of PAD was 4.1±0.2% and the prevalence of PN was 12.0±0.5%. The prevalence of elevated NT-proBNP (≥125 ng/L), hs-troponin T (≥6 ng/L), and hs-troponin I (≥6 ng/L for men and ≥4 ng/L for women) was 54.0±3.4%, 73.9±3.5%, and 32.3±3.7%, respectively, among adults with PAD and 32.9±1.9%, 72.8±2.0%, and 22.7±1.9%, respectively, among adults with PN. There was a strong, graded association of higher clinical categories of NT-proBNP with PAD after adjusting for cardiovascular risk factors. Clinical categories of elevated hs-troponin T and hs-troponin I were strongly associated with PN in adjusted models. After a maximum follow-up of 21 years, elevated NT-proBNP, hs-troponin T, and hs-troponin I were each associated with all-cause and cardiovascular mortality, with higher risks of death observed among adults with elevated cardiac biomarkers plus PAD or PN compared with elevated biomarkers alone. Our study establishes a high burden of subclinical cardiovascular disease defined by cardiac biomarkers in people with PAD or PN. Cardiac biomarkers provided prognostic information for mortality within and across PAD and PN status, supporting the use of these biomarkers for risk stratification among adults without prevalent cardiovascular disease.

Angiogenic Growth Factors and Their Predictive Role in Patients With Peripheral Arterial Disease

Peripheral artery disease (PAD) is a chronic cardiovascular disease that results in catastrophic consequences, such as lower-extremity amputations, adverse cardiovascular events, and even death. Research has been sparse with regards to tools that can aid physicians with prognostication and risk-stratification of patients with PAD. To identify PAD-specific prognostic biomarkers, in this study, we investigated several proteins involved in angiogenesis with the aim of studying their potential role in predicting major adverse limb effects (MALE) and worsening PAD status (define as drop in ankle-brachial index [ABI] by over 0.15) in patients with PAD. Blood samples were collected from consecutive patients with PAD (n = 250) and without PAD (n = 125) presenting to St Michael's Hospital (Toronto, Canada) who were then prospectively followed for 36 months (3 years). Levels of 17 circulatory proteins involved in angiogenesis proteins were quantified. The primary outcome of this study was MALE (a composite of need for vascular intervention [open or endovascular] or major amputation), whereas the secondary outcome was worsening PAD status (defined as drop in ABI ≥0.15). Multivariable regression analyses were performed to control for potential confounding factors and ascertain the prognostic value of angiogenesis-related proteins in predicting MALE (primary outcome) and worsening PAD status/disease progression (secondary outcome). Survival analyses were conducted to assess freedom from MALE and worsening PAD status. Compared with non-PAD patients, eight angiogenesis-related proteins were differentially expressed in patients with PAD. The primary outcome (MALE) and the secondary outcome (worsening PAD status) were observed in 83 (22%) and 52 (14%) patients, respectively. Of the eight proteins differentially expressed, the most reliable predictor of MALE was hepatocyte growth factor (HGF) (adjusted hazard ratio (aHR) of 0.79 (95% confidence interval [CI], 0.15-0.86). Due to the predictive potential of HGF, we stratified patients into two groups based on their HGF levels: (1) high GHF and (2) low HGF. Relative to patients with high HGF, patients with low HGF had a lower 3-year freedom from MALE (66% vs 88%; P = .001), vascular intervention (68% vs 88%; P = .001), major amputation (93% vs 98%; P = .023), and worsening PAD status (81% vs 91%; P = .006). Based on these data, HGF proteins shows potential in serving as a PAD-specific prognostic biomarker that can help physicians identify PAD patients at risk of MALE.

Heart failure, peripheral artery disease, and dapagliflozin: a patient-level meta-analysis of DAPA-HF and DELIVER.

Because an increased risk of amputation with canagliflozin was reported in the CANVAS trials, there has been a concern about the safety of sodium-glucose cotransporter 2 inhibitors in patients with peripheral artery disease (PAD) who are at higher risk of amputation. A patient-level pooled analysis of the DAPA-HF and DELIVER trials, which evaluated the efficacy and safety of dapagliflozin in patients with heart failure (HF) with reduced, mildly reduced/preserved ejection fraction, respectively, was conducted. In both trials, the primary outcome was the composite of worsening HF or cardiovascular death, and amputation was a prespecified safety outcome. Peripheral artery disease history was available for 11 005 of the total 11 007 patients. Peripheral artery disease was reported in 809 of the 11 005 patients (7.4%). Median follow-up was 22 months (interquartile range 17-30). The rate of the primary outcome (per 100 person-years) was higher in PAD patients than that in non-PAD patients: 15.1 [95% confidence interval (CI) 13.1-17.3) vs. 10.6 (10.2-11.1]; adjusted hazard ratio 1.23 (95% CI 1.06-1.43). The benefit of dapagliflozin on the primary outcome was consistent in patients with [hazard ratio 0.71 (95% CI 0.54-0.94)] and without PAD [0.80 (95% CI 0.73-0.88)] (Pinteraction = 0.39). Amputations, while more frequent in PAD patients, were not more common with dapagliflozin, compared with placebo, irrespective of PAD status (PAD, placebo 4.2% vs. dapagliflozin 3.7%; no PAD, placebo 0.4% vs. dapagliflozin 0.4%) (Pinteraction = 1.00). Infection rather than ischaemia was the main trigger for amputation, even in patients with PAD. The risk of worsening HF or cardiovascular death was higher in patients with PAD, as was the risk of amputation. The benefits of dapagliflozin were consistent in patients with and without PAD, and dapagliflozin did not increase the risk of amputation.

Abstract P624: Peripheral Artery Disease and Long-Term Risk of Femur Fracture Among Older Adults: The Atherosclerosis Risk in Communities Study

Introduction: Femur fracture can have devastating consequences in older patients. Lower extremity peripheral artery disease (PAD) reduces physical function, which can in turn increase the risk of falls. However, less is known regarding the association of PAD with incident femur fracture in older adults. Hypothesis: PAD is associated with a higher risk of incident femur fracture independent of potential confounders. Methods: We included 5,276 participants from ARIC Visit 5 (2011-2013) (mean age 76 [standard deviation: 5] years, 57% women and 22% self-identified Black race). Femur fractures were defined as an outpatient encounter or hospitalization with ICD-9 codes: 820-821 or ICD-10 codes: S72. We quantified the association of PAD status at baseline, based on ankle-brachial index (ABI) ≤0.9 or clinical history of PAD, with incident femur fracture using multivariable Cox regression and follow-up until 2019. Results: There were 224 incident femur fractures over a median follow-up of 7.2 [IQI 5.6-7.8] years. The incidence rate of femur fracture was almost 2-times higher in participants with PAD compared to those without a history of PAD and ABI 1.11-1.20 (reference group) (10.5 [7.5-14.8] vs. 5.5 [4.3-6.9] per 1,000 person-years). This association persisted after accounting for demographic (hazards ratio [HR]: 1.86 [95% CI 1.23-2.84] in Model 1) and other confounders (HR 1.59 [1.04-2.46] in Model 2) (Table). When we excluded participants with a clinical history of PAD, low ABI (≤0.9) remained significantly associated with incident femur fracture compared to the reference group (HR 1.94 [1.18-3.19]). Our findings were consistent in demographic and clinical subgroups (e.g., by sex and diabetes status). Conclusions: In community-dwelling older adults, PAD, even when not clinically diagnosed, was associated with an increased risk of femur fracture. Clinicians and patients should be aware of this complication of PAD and consider preventive measures to avoid falls (e.g., exercise counseling, and making home safer).

Abstract P105: Peripheral Artery Disease and Subsequent Risk of Cancer: The Atherosclerosis Risk in Communities (ARIC) Study

Introduction: Cardiovascular disease (CVD) and cancer share risk factors, including smoking and obesity. Indeed, an increased cancer risk was reported among patients with CVD, such as myocardial infarction. Lower extremity peripheral artery disease (PAD) has also been explored in this context, but most previous studies included only Whites, had follow-up &lt;10 years, or did not account for key confounders like smoking. Hypothesis: PAD is independently associated with long-term cancer risk in a bi-racial cohort. Methods: We studied 13,102 ARIC participants without prevalent cancer at visit 1 (1987-89) (mean age 54 [SD 6] years, 54% women, and 26% Black) (funding: NHLBI, NCI, and NPCR). Incident cancer was ascertained by linkage to cancer registries and medical record review. We categorized PAD status at visit 1 into symptomatic PAD (intermittent claudication or a history of lower extremity revascularization), asymptomatic PAD (ankle brachial index [ABI] ≤0.9), and other ABI categories of &gt;0.9-1.0, &gt;1.0-1.1, &gt;1.1-1.2, &gt;1.2-1.3 and &gt;1.3. We ran multivariable Cox models. Results: During the median follow-up of 25 years (IQI 15-27 years), there were 4,142 incident cancer cases. 25-year cumulative cancer incidence was 48% in symptomatic PAD, 39% in asymptomatic PAD, and 31-34% in the other categories. When we adjusted for demographic factors, both symptomatic and asymptomatic PAD showed significant hazard ratios for incident cancer (1.79 [95%CI 1.33-2.43] and 1.39 [1.18-1.63], respectively, vs. ABI 1.1-1.2, Model 1 in Table ). After adjusting for additional potential confounders, including smoking and diabetes, these associations were somewhat attenuated but remained consistent (Models 2-4 in Table ). Conclusion: Both symptomatic and asymptomatic PAD were associated with an increased risk of cancer independently of smoking and diabetes. Although potential mechanisms should be explored, clinicians should be aware of this excess cancer risk among patients with PAD when considering cancer prevention and screening.

The prognostic capability of inflammatory proteins in predicting peripheral artery disease related adverse events.

Levels of inflammatory proteins and their prognostic potential have been inadequately studied in patients with peripheral artery disease (PAD). In this study, we quantified and assessed the ability of inflammatory proteins in predicting PAD-related adverse events. In this prospective case-control study, blood samples were collected from patients without PAD (n = 202) and patients with PAD (n = 275). The PAD cohort was stratified by disease severity based on ankle brachial index (ABI): mild (n = 49), moderate (n = 164), and severe (n = 62). Patients were followed for 2 years. Plasma concentrations of 5 inflammatory proteins were measured: Alpha-2-Macroglobulin (A2M), Fetuin A, Alpha-1-Acid Glycoprotein (AGP), Serum Amyloid P component (SAP), and Adipsin. The primary outcome of our study was major adverse limb event (MALE), defined as the need for vascular intervention (open or endovascular revascularization) or major amputation. The secondary outcome was worsening PAD status, defined as a drop in ABI greater than or equal to 0.15 over the study period. Multivariable logistic regression was performed to assess the prognostic value of inflammatory proteins in predicting MALE, adjusting for confounding variables. Compared to patients without PAD, three inflammatory proteins were differentially expressed in patients with PAD (AGP, Fetuin A, and SAP). The primary outcome (MALE) and secondary outcome (worsening PAD) status were noted in 69 (25%) and 60 (22%) patients, respectively. PAD-related adverse events occurred more frequently in severe PAD patients. Based on our data, the inflammatory protein AGP was the most reliable predictor of primary and secondary outcomes. On multivariable analysis, there was a significant association between AGP and MALE in all PAD disease states [mild: adjusted HR 1.13 (95% CI 1.05-1.47), moderate: adjusted HR 1.23 (95% CI 1.16-1.73), severe: adjusted HR 1.37 (95% CI 1.25-1.85)]. High levels of AGP were associated with lower 2-year MALE-free survival in all PAD disease states [mild (64% vs. 100%, p = 0.02), moderate (64% vs. 85%, p = 0.02), severe (55% vs. 88%, p = 0.02), all PAD (62% vs. 88%, p = 0.01)]. Levels of inflammatory protein AGP may help in risk stratifying PAD patients at high risk of MALE and worsening PAD status and subsequently facilitate further vascular evaluation and initiation of aggressive medical/surgical management.

Peripheral Artery Disease and Subsequent Risk of Infectious Disease in Older Individuals: The ARIC Study

ObjectiveTo quantify the association of peripheral artery disease (PAD) with infection risk because PAD has been understudied despite recognition of atherosclerotic cardiovascular disease as a risk factor for infection. MethodsAmong 5082 participants of the Atherosclerosis Risk in Communities study (aged 71 to 90 years during 2011-2013), we assessed the association of PAD status, based on clinical history and ankle-brachial index (ABI), with infection-related hospitalization (through December 2019) using multivariable Cox regression. We also cross-classified participants by PAD and coronary heart disease (CHD)/stroke status at baseline, with implications for polyvascular disease. ResultsDuring the median follow-up of 6.5 years, there were 1677 infection-related hospitalizations. Peripheral artery disease (clinical history or ABI ≤0.90) was independently associated with the risk of overall infection (adjusted hazard ratio [HR], 1.66 [95% CI, 1.42 to 1.94] vs ABI of 1.11 to 1.20), as was borderline low ABI of 0.91 to 1.00 (adjusted HR, 1.75 [95% CI, 1.47 to 2.07]). Results were consistent across major types of infection (ie, cellulitis, bloodstream infection, pneumonia, and urinary tract infection). For overall infection, PAD plus CHD/stroke had the highest HR of hospitalized infection (1.9), and PAD alone and CHD/stroke alone showed similar HRs of 1.6. For subtypes of infection, PAD alone had the highest HR of approximately 2 for bloodstream infection; PAD alone and PAD plus CHD/stroke had a similar risk of urinary tract infection with HR of approximately 1.7. ConclusionPeripheral artery disease and borderline low ABI were robustly associated with infection-related hospitalization of older adults. The contribution of PAD to infection risk was comparable to that of CHD/stroke, warranting clinical attention to PAD for the prevention of infectious diseases.

Genetic evidence for a causal relationship between type 2 diabetes and peripheral artery disease in both Europeans and East Asians

BackgroundObservational studies have revealed that type 2 diabetes (T2D) is associated with an increased risk of peripheral artery disease (PAD). However, whether the two diseases share a genetic basis and whether the relationship is causal remain unclear. It is also unclear as to whether these relationships differ between ethnic groups.MethodsBy leveraging large-scale genome-wide association study (GWAS) summary statistics of T2D (European-based: Ncase = 21,926, Ncontrol = 342,747; East Asian-based: Ncase = 36,614, Ncontrol = 155,150) and PAD (European-based: Ncase = 5673, Ncontrol = 359,551; East Asian-based: Ncase = 3593, Ncontrol = 208,860), we explored the genetic correlation and putative causal relationship between T2D and PAD in both Europeans and East Asians using linkage disequilibrium score regression and seven Mendelian randomization (MR) models. We also performed multi-trait analysis of GWAS and two gene-based analyses to reveal candidate variants and risk genes involved in the shared genetic basis between T2D and PAD.ResultsWe observed a strong genetic correlation (rg) between T2D and PAD in both Europeans (rg = 0.51; p-value = 9.34 × 10−15) and East Asians (rg = 0.46; p-value = 1.67 × 10−12). The MR analyses provided consistent evidence for a causal effect of T2D on PAD in both ethnicities (odds ratio [OR] = 1.05 to 1.28 for Europeans and 1.15 to 1.27 for East Asians) but not PAD on T2D. This putative causal effect was not influenced by total cholesterol, body mass index, systolic blood pressure, or smoking initiation according to multivariable MR analysis, and the genetic overlap between T2D and PAD was further explored employing an independent European sample through polygenic risk score regression. Multi-trait analysis of GWAS revealed two novel European-specific single nucleotide polymorphisms (rs927742 and rs1734409) associated with the shared genetic basis of T2D and PAD. Gene-based analyses consistently identified one gene ANKFY1 and gene-gene interactions (e.g., STARD10 [European-specific] to AP3S2 [East Asian-specific]; KCNJ11 [European-specific] to KCNQ1 [East Asian-specific]) associated with the trans-ethnic genetic overlap between T2D and PAD, reflecting a common genetic basis for the co-occurrence of T2D and PAD in both Europeans and East Asians.ConclusionsOur study provides the first evidence for a genetically causal effect of T2D on PAD in both Europeans and East Asians. Several candidate variants and risk genes were identified as being associated with this genetic overlap. Our findings emphasize the importance of monitoring PAD status in T2D patients and suggest new genetic biomarkers for screening PAD risk among patients with T2D.

Outcomes After Acute Coronary Syndrome in Patients With Diabetes Mellitus and Peripheral Artery Disease (from the TRACER, TRILOGY-ACS, APPRAISE-2, and PLATO Clinical Trials)

Patients with acute coronary syndrome (ACS) are at risk for recurrent adverse events, and multiple reports suggest that this risk is increased in patients with concomitant diabetes mellitus (DM) and peripheral artery disease (PAD). The aim of this article was to investigate cardiovascular outcomes in patients with DM presenting with ACS, stratified by PAD status. Data were derived from 4 randomized post-ACS trials (PLATO [Platelet Inhibition and Patient Outcomes], APPRAISE-2 p Apixaban for Prevention of Acute Ischemic Events 2], TRILOGY [Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage], and TRACER [Thrombin Receptor Agonist for Clinical Event Reduction in Acute Coronary Syndrome]). Using Cox regression analysis, we investigated major adverse cardiovascular events (MACEs), a composite of cardiovascular mortality, myocardial infarction (MI), or stroke and the individual components of MACE and all-cause mortality in patients with DM, presenting with ACS, stratified by PAD status as the risk modifier. This study included 15,387 patients with a diagnosis of DM and ACS, of whom 1,751 had an additional diagnosis of PAD. PAD was associated with more than doubled rates of MACE (hazard ratio [HR] 2.03, 95% confidence interval [CI] 1.81 to 2.27), all-cause mortality (HR 2.48, 95% CI 2.14 to 2.87), cardiovascular mortality (HR 2.42, 95% CI 2.04 to 2.86), and MI (HR 2.07, 95% CI 1.79 to 2.38). Patients with both PAD and DM were also more optimally treated with antihypertensive, antidiabetic, and statin medication at baseline. In conclusion, this analysis of 4 major post-ACS trials showed that patients with DM and PAD had a substantially higher risk of MACE, cardiovascular mortality, all-cause mortality, and MI despite being optimally treated with guideline-based therapies.

Machine learning-based classification of arterial spectral waveforms for the diagnosis of peripheral artery disease in the context of diabetes: A proof-of-concept study.

Point-of-care duplex ultrasound has emerged as a promising test for the diagnosis of peripheral artery disease (PAD). However, the interpretation of morphologically diverse Doppler arterial spectral waveforms is challenging and associated with wide inter-observer variation. The aim of this study is to evaluate the utility of machine learning techniques for the diagnosis of PAD from Doppler arterial spectral waveforms sampled at the level of the ankle in patients with diabetes. In two centres, 590 Doppler arterial spectral waveform images (PAD 369, no-PAD 221) from 305 patients were prospectively collected. Doppler arterial spectral waveform signals were reconstructed. Blinded full lower-limb reference duplex ultrasound results were used to label waveform according to PAD status (i.e., PAD, no-PAD). Statistical metrics and multiscale wavelet variance were extracted as discriminatory features. A long short-term memory (LSTM) network was used for the classification of raw signals, and logistic regression (LR) and support vector machines (SVM) were used for classification of extracted features. Signals and feature vectors were randomly divided into training (80%) and testing (20%) sets. The highest overall accuracy was achieved using a logistic regression model with a combination of statistical and multiscale wavelet variance features, with 88% accuracy, 92% sensitivity, and 82% specificity. The area under the receiver operating characteristics curve (AUC) was 0.93. We have constructed a machine learning algorithm with high discriminatory ability for the diagnosis of PAD using Doppler arterial spectral waveforms sampled at the ankle vessels.

Urinary Cystatin C Has Prognostic Value in Peripheral Artery Disease.

Despite its association with adverse outcomes, peripheral artery disease (PAD) remains undertreated. Cystatin C is elevated in patients with renal disease and may be a marker of cardiovascular disease. We examined the prognostic ability of urinary Cystatin C (uCystatinC) in predicting adverse PAD-related events. In this prospective case-control study, urine samples were collected from patients with PAD (n = 121) and without PAD (n = 77). The cohort was followed for 2 years. uCystatinC was normalized to urinary creatinine (uCr) (uCystatinC/uCr; μg/g). The primary outcome was major adverse limb event (MALE; composite of vascular intervention (open or endovascular) or major limb amputation). The secondary outcome was worsening PAD status (drop in ABI ≥ 0.15). Multivariable Cox regression and Kaplan–Meier analyses were performed to assess the prognostic value of uCystatinC/uCr with regards to predicting MALE and worsening PAD status. Our analysis demonstrated that patients with PAD had significantly higher median [IQR] uCystatinC/uCr levels (24.9 μg/g [14.2–32.9] vs. 20.9 μg/g [11.1–27.8], p = 0.018). Worsening PAD status and MALE were observed in 39 (20%) and 34 (17%) patients, respectively. uCystatinC/uCr predicted worsening PAD status with a hazard ratio (HR) of 1.78 (95% CI 1.12–2.83, p = 0.015), which persisted after controlling for baseline demographic and clinical characteristics (adjusted HR 1.79 [95% CI 1.11–2.87], p = 0.017). Patients with high uCystatinC/uCr had a lower 2-year freedom from MALE (77% vs. 89%, p = 0.025) and worsening PAD status (63% vs. 87%, p = 0.001). Based on these data, higher uCystatinC/uCr levels are associated with adverse PAD-related events and have prognostic value in risk-stratifying individuals for further diagnostic vascular evaluation or aggressive medical management.

Urinary Fatty Acid Binding Protein 3 Has Prognostic Value in Peripheral Artery Disease.

BackgroundDespite its significant association with limb loss and death, peripheral artery disease (PAD) remains underdiagnosed and undertreated. The current accepted gold-standard for PAD screening, the ankle brachial index (ABI), is limited by operator dependence, erroneous interpretation, and unreliability in patients with diabetes. Fatty acid binding protein 3 (FABP3) is an intracellular protein that becomes released into circulation and excreted into urine following skeletal muscle injury. We examined the prognostic ability of urinary FABP3 (uFABP3) in predicting adverse PAD-related events.MethodsIn this prospective case-control study, urine samples were collected from patients with PAD (n = 142) and without PAD (n = 72). The cohort was followed for 2 years. uFABP3 was normalized to urinary creatinine (uCr) (uFABP3/uCr). The primary outcome was major adverse limb event (MALE; composite of vascular intervention [open or endovascular] or major limb amputation). The secondary outcome was worsening PAD status (drop in ABI≥0.15). Cox regression analyses with multivariable adjustment for baseline demographic and clinical variables were performed to assess the prognostic value of uFABP3/uCr with regards to predicting MALE and worsening PAD status.ResultsPatients with PAD had significantly higher median [IQR] uFABP3/uCr levels (3.46 [2.45–6.90] vs. 2.61 [1.98–4.62], p = 0.001). MALE and worsening PAD status were observed in 21 (10%) and 28 (14%) patients, respectively. uFABP3/uCr predicted MALE and worsening PAD status with adjusted hazard ratios (HR) of 1.28 (1.16–1.41, p = 0.001) and 1.16 (1.02–1.27, p = 0.021), respectively. Patients with high uFABP3/uCr had a lower 2-year freedom from MALE (86 vs. 96%, p = 0.047) and worsening PAD status (78 vs. 99%, p = 0.001). There was good discriminatory ability for uFABP3/uCr in predicting the primary outcome of MALE, with an area under the receiver operating characteristics curve (AUROC) of 0.78.ConclusionsMeasuring uFABP3/uCr levels in patients with PAD can help identify those at high risk of adverse PAD-related events. This study highlights the prognostic value of uFABP3 in risk-stratifying individuals for further diagnostic vascular evaluation or aggressive medical management.

The Clinical Utility of D-Dimer and Prothrombin Fragment (F1+2) for Peripheral Artery Disease: A Prospective Study.

D-dimer and prothrombin fragment (F1+2) levels are elevated in patients with peripheral artery disease (PAD). We examined their prognostic potential in predicting decreasing ABI and major adverse limb events (MALE). A total of 206 patients were recruited from St. Michael’s Hospital and followed for two years. Baseline plasma concentrations of D-dimer and F1+2 were recorded. Pearson’s correlation was used to assess the correlation between the biomarkers and ABI at year 2. During follow-up, multivariable Cox proportional hazard analysis was performed to investigate their role in predicting decreasing ABI (defined as change in ABI > −0.15) and MALE (defined as the need for arterial intervention or major limb amputation). Cumulative survival was assessed using Kaplan–Meier analysis. Baseline D-dimer and F1+2 levels were elevated in PAD patients (median (IQR) 1.34 (0.80–2.20) for D-dimer and 3.60 (2.30–4.74) for F1+2; p = 0.001) compared to non-PAD controls (median (IQR) 0.69 (0.29–1.20) for D-dimer and 1.84 (1.17–3.09) for F1+2; p = 0.001). Both markers were negatively correlated with ABI at year 2 (r = −0.231 for D-dimer, r = −0.49 for F1+2; p = 0.001). Cox analysis demonstrated F1+2 and D-dimer to be independent predictors of PAD status (HR = 1.27, 95% CI = 1.15–1.54; p = 0.013 for D-dimer and HR = 1.28, 95% CI = 1.14–1.58; p = 0.019 for F1+2). Elevated baseline concentrations of D-dimer and F1+2 were associated with high incidence of decreasing ABI and 1- and 2-year event-free survival (62% and 86%, respectively). Combined analysis of D-dimer and F1+2 provides important prognostic information that facilitates risk stratification for future disease progression and MALE outcomes in patients with PAD.

Cardiovascular efficacy of liraglutide and semaglutide in individuals with diabetes and peripheral artery disease.

AimTo evaluate the cardiovascular (CV) efficacy of liraglutide and semaglutide in patients with type 2 diabetes (T2D) and peripheral artery disease (PAD).Materials and MethodsLEADER and SUSTAIN 6 trials investigated subcutaneous liraglutide (≤1.8 mg/day) and semaglutide (0.5 or 1.0 mg/week), respectively, versus placebo in patients with T2D and high CV risk (median follow‐up: 3.8 and 2.1 years, respectively). The primary outcome was a composite of CV death, non‐fatal myocardial infarction or non‐fatal stroke (major adverse CV event [MACE]) according to the presence of PAD at baseline.ResultsOverall, 1184/9340 (12.7%) patients in LEADER and 460/3297 (14.0%) in SUSTAIN 6 had PAD at baseline. Patients with PAD were at an ~35% increased risk of MACE versus those without (LEADER: hazard ratio [HR] 1.36, 95% confidence interval [CI] 1.17‐1.58; SUSTAIN 6: HR 1.33, 95% CI 0.94‐1.83). The effects of both therapies on MACE were consistently beneficial in patients with PAD (liraglutide: HR 0.77, 95% CI 0.58‐1.01; semaglutide: 0.61, 0.33‐1.13) and without (liraglutide: HR 0.89, 95% CI 0.79‐1.00; semaglutide: HR 0.77, 95% CI 0.58‐1.01; P interaction = .34 for liraglutide and .49 for semaglutide). Absolute risk reductions for MACE were higher in patients with PAD (liraglutide: 4.13%‐point, 95% CI −0.15‐8.42; semaglutide: 4.63%‐point, 95% CI −0.58‐9.84) versus without (liraglutide:1.42%‐point, 95% CI −0.03‐2.87; semaglutide: 1.90%‐point, 95% CI 0.00‐3.80).ConclusionBoth liraglutide and semaglutide reduce MACE with consistent CV efficacy regardless of PAD status.

Ischaemic and bleeding risk in atrial fibrillation with and without peripheral artery disease and efficacy and safety of full- and half-dose edoxaban vs. warfarin: insights from ENGAGE AF-TIMI 48.

In patients with atrial fibrillation (AF), peripheral artery disease (PAD) is associated with higher rates of stroke and bleeding. Both higher dose edoxaban (60/30mg) and lower dose edoxaban (30/15mg) were non-inferior to warfarin for stroke and systemic embolism (SSE) and significantly reduced major bleeding in AF patients in the global study to assess the safety and effectiveness of edoxaban vs standard practice of dosing with warfarin in patients with atrial fibrillation (ENGAGE AF-TIMI 48) trial. Whether the efficacy and safety of these dosing strategies vs. warfarin are consistent in patients with AF and PAD has not been described. Of 21 105 patients with AF randomized to warfarin, edoxaban 60/30mg, or edoxaban 30/15mg, 841 were identified with PAD. Endpoints included major adverse cardiovascular events (MACEs), SSE, and major bleeding. Patients with PAD had higher risk of MACEs [adjusted hazard ratio (HRadj) 1.33, 95% confidence interval (CI) 1.12-1.57, P = 0.001] and cardiovascular (CV) death (HRadj 1.49, 95% CI 1.21-1.83, P &lt; 0.001) than those without PAD, but not major bleeding. The efficacy of edoxaban 60/30mg vs. warfarin was consistent regardless of PAD (SSE HR; PAD 1.16, 95% CI 0.42-3.20; no-PAD 0.86, 95% CI 0.74-1.02, P-interaction 0.57) as was major bleeding (PAD 0.96, 95% CI 0.54-1.70; no-PAD 0.80, 95% CI 0.70-0.91, P-interaction 0.54). Edoxaban 30/15mg was inferior for SSE, with significant heterogeneity when stratified by PAD status (P-interaction 0.039). Patients with AF and PAD are at heightened risk of MACEs and CV death vs. those without PAD. The efficacy and safety of edoxaban 60/30mg vs. warfarin in AF are consistent regardless of PAD; however, edoxaban 30/15mg is inferior for stroke prevention in AF patients with PAD. Clinical Trial Registration: ClinicalTrials.gov identifier: NCT00781391.

Daily Step Counts in Participants With and Without Peripheral Artery Disease.

We compared the prevalence of participants with and without symptomatic peripheral artery disease (PAD) who met the goals of attaining >7000 and 10 000 steps/d, and we determined whether PAD status was significantly associated with meeting the daily step count goals before and after adjusting for demographic variables, comorbid conditions, and cardiovascular risk factors. Participants with PAD (n = 396) and without PAD (n = 396) were assessed on their walking for 7 consecutive days with a step activity monitor. The PAD group took significantly fewer steps/d than the non-PAD control group (6722 ± 3393 vs. 9475 ± 4110 steps/d; P < .001). Only 37.6% and 15.7% of the PAD group attained the goals of walking >7000 and 10 000 steps/d, respectively, whereas 67.9% and 37.4% of the control group attained these goals (P < .001 for each goal). Having PAD was associated with a 62% lower chance of attaining 7000 steps/d than compared with the control group (OR = 0.383; 95% CI, 0.259-0.565; P < .001), and a 55% lower chance of attaining 10 000 steps/d (OR = 0.449; 95% CI, 0.282-0.709; P < .001). Significant covariates (P < .01) included age, current smoking, diabetes, and body mass index. Participants with symptomatic PAD had a 29% lower daily step count compared with age- and sex-matched controls, and were less likely to attain the 7000 and 10 000 steps/d goals. Additionally, participants who were least likely to meet the 7000 and 10 000 daily step count recommendations included those who were older, currently smoked, had diabetes, and had higher body mass index.

Model-Based Algorithms for Detecting Peripheral Artery Disease Using Administrative Data From an Electronic Health Record Data System: Algorithm Development Study.

BackgroundPeripheral artery disease (PAD) affects 8 to 10 million Americans, who face significantly elevated risks of both mortality and major limb events such as amputation. Unfortunately, PAD is relatively underdiagnosed, undertreated, and underresearched, leading to wide variations in treatment patterns and outcomes. Efforts to improve PAD care and outcomes have been hampered by persistent difficulties identifying patients with PAD for clinical and investigatory purposes.ObjectiveThe aim of this study is to develop and validate a model-based algorithm to detect patients with peripheral artery disease (PAD) using data from an electronic health record (EHR) system.MethodsAn initial query of the EHR in a large health system identified all patients with PAD-related diagnosis codes for any encounter during the study period. Clinical adjudication of PAD diagnosis was performed by chart review on a random subgroup. A binary logistic regression to predict PAD was built and validated using a least absolute shrinkage and selection operator (LASSO) approach in the adjudicated patients. The algorithm was then applied to the nonsampled records to further evaluate its performance.ResultsThe initial EHR data query using 406 diagnostic codes yielded 15,406 patients. Overall, 2500 patients were randomly selected for ground truth PAD status adjudication. In the end, 108 code flags remained after removing rarely- and never-used codes. We entered these code flags plus administrative encounter, imaging, procedure, and specialist flags into a LASSO model. The area under the curve for this model was 0.862.ConclusionsThe algorithm we constructed has two main advantages over other approaches to the identification of patients with PAD. First, it was derived from a broad population of patients with many different PAD manifestations and treatment pathways across a large health system. Second, our model does not rely on clinical notes and can be applied in situations in which only administrative billing data (eg, large administrative data sets) are available. A combination of diagnosis codes and administrative flags can accurately identify patients with PAD in large cohorts.

Underuse of Cardiovascular Medications in Individuals With Known Lower Extremity Peripheral Artery Disease: HCHS/SOL.

BackgroundUnderuse of cardiovascular medications for secondary prevention among individuals with peripheral artery disease (PAD) has been reported. Little is known about PAD treatment status in the Hispanic/Latino population in the United States, who may have limited access to health care and who have worse clinical outcomes than non‐Hispanic individuals.Methods and ResultsWe studied the use of cardiovascular therapies in 1244 Hispanic/Latino individuals recruited from 4 sites in the United States, including 826 individuals who reported diagnosis of PAD by physician and 418 individuals with coronary artery disease alone, in the Hispanic Community Health Study/Study of Latinos. We compared the prevalence of using antiplatelet therapy, lipid‐lowering therapy and antihypertensive therapy by PAD and coronary artery disease status. Among those with PAD, we studied factors associated with taking cardiovascular medications, including demographic and socioeconomic factors, acculturation, access to health care and comorbidities, using multivariable regression models. The overall prevalence for individuals with PAD taking antiplatelet therapy, lipid‐lowering therapy and, among hypertensive individuals, antihypertensive therapy was 31%, 26% and 57%, respectively. Individuals of Mexican background had the lowest use for all classes of cardiovascular medications. Older age, number of doctor visits and existing hypertension and diabetes mellitus were significantly associated with taking cardiovascular therapies in adjusted models. Compared with those with PAD alone, individuals with PAD and concurrent coronary artery disease were 1.52 (95% CI, 1.20–1.93) and 1.74 (1.30–2.32) times more likely to use antiplatelet agents and statins according to multivariable analysis. No significant difference of antihypertensive medication use was found among PAD patients with or without coronary artery disease.ConclusionsHispanic/Latino individuals with known PAD underuse cardiovascular medications recommended in clinical guidelines. More efforts should be directed to improve treatment in this important group.