Events In Peripheral Arterial Disease Patients Research Articles

Abstract 12634: Amplified P2x 3 Pathway Activity in IB4 Positive Muscle DRG Neurons and Exercise Pressor Reflex Regulation in Hindlimb Ischemia-Reperfusion

Background: Hindlimb ischemia-reperfusion (IR) represents one of the most prominent pathological conditions observed in peripheral artery disease (PAD). Arterial blood pressure response (BP) during exercise, partly driven by the exaggerated exercise pressor reflex (EPR), is associated with an elevated risk of cardiovascular events in PAD patients. However, the precise underlying mechanisms leading to this exaggerated BP response are poorly elucidated. The purinergic P2X 3 signaling pathway, which plays a key role in modifying the EPR, was the focus of the present study. Objectives: To examine the regulatory role of P2X 3 on the EPR in a rat model of hindlimb IR, which was induced by 6 hours’ ischemia followed by 18 hours’ reperfusion (referred to as IR rats). Results: We found that, in IR rats, there were: 1) upregulation of P2X 3 protein expression in the L4-6 dorsal root ganglion (DRG) (1.48±0.16 in IR rats/n=8 vs. 1.00±0.41 in sham rats/n=9; P<0.05), which was localized in IB4 positive DRG neurons by the method of immunohistochemistry, 2) amplified P2X currents in isolated muscle DRG neurons (P2X transient currents: 1281.64±776.74 pA in IR rats/n=25, vs. 717.91±556.2 pA in sham rats/n=9, P<0.05; and sustain currents: 466.94±168.68 pA in IR rats/n=11, vs. 271.49±200.90 pA in sham rats/n=8, P<0.05); 3) amplification of P2X-mediated BP response (29±8 mmHg in IR rats/n=12 vs. 21±4 mmHg in sham rats/n=7; P<0.05); and 4) alleviation of the exaggerated BP response induced by static muscle contraction (18±8 mmHg in IR +A317491/n=8, vs. 29±11 mmHg in IR/n=7, P<0.05) and P2X-mediated BP response by α, β-me-ATP injection (15±4 mmHg in IR+A317491 /n=6 vs. 23±7 mmHg in IR/n=4, P<0.05) following the inhibition of muscle afferents’ P2X 3 receptor by A-317491. We further verified that both A-317491 and siRNA knockdown of P2X 3 significantly decreased the activity of P2X currents in the isolated muscle DRG neurons (all P<0.05 vs. their respective controls). Conclusion: With the above evidence from multiple approaches, we concluded that the P2X 3 signaling pathway activity is amplified following hindlimb IR via the enhancing expression and activity of P2X 3 receptors in IB4 positive muscle DRG afferents. This contributes to the exacerbated EPR responses in PAD.

Fifteen-year clinical prognosis and cardiovascular or limb event associated with homocysteine levels in peripheral arterial disease

BackgroundThere are limited reports on the relationship between plasma homocysteine (Hcy) levels and long-term all-cause death (ACD), cardiovascular events, or limb events in patients with peripheral arterial disease (PAD). We examined the relationship between plasma Hcy levels and 15-year these events in PAD patients. MethodsWe performed a prospective cohort study in 955 PAD patients. The patients were divided into four groups based on plasma Hcy levels with median (interquartile range). The endpoints were cumulative incidences of ACD, major adverse cardiovascular events (MACE), and MACE plus limb events (MACLE). ResultsThe incidences of ACD, MACE, and MACLE were correlated with plasma Hcy levels (P < 0.05). In multiple regression analysis, plasma Hcy had positive correlations with C-reactive protein (CRP), men, and critical limb ischemia (CLI) and negative correlations with estimated glomerular filtration rate (eGFR) and high-density lipoprotein cholesterol (p < 0.05). In Cox multivariate analysis, higher Hcy (HR 1.614, 95 % CI 1.229–2.119, p = 0.001), age, CRP, brain natriuretic peptide (BNP), D-dimer, lower body mass index, ankle brachial pressure index (ABI), serum albumin, eGFR, CLI, coronary heart disease (CHD), cerebrovascular disease, and diabetes were related to ACD; higher Hcy (HR 1.242, 95 % CI 1.004–1.535, p = 0.045), age, BNP, lower ABI, serum albumin, diabetes, and CHD were related to MACE; and higher Hcy (HR 1.290, 95 % CI 1.057–1.574, p = 0.012), BNP, lower ABI, serum albumin, CHD, and diabetes were related to MACLE (P < 0.05). Statins improved ACD, MACE, and MACLE (p < 0.01). ConclusionsPlasma Hcy was a risk factor for 15-year ACD, MACE, and MACLE in patients with PAD.

Antithrombotic therapy in peripheral arterial disease

BackgroundPatients with peripheral arterial disease (PAD) are at increased risk for major adverse cardiovascular events (MACE) such as cardiovascular death, myocardial infarction, and stroke as well as major adverse limb events (MALE) such as amputation and acute limb ischemia. Therefore, prevention of thrombotic events is crucial to improve the prognosis of PAD patients. This review article concludes current evidence and guideline recommendations about antithrombotic therapy in PAD patients.Antithrombotic therapy is highly effective to reduce MACE and MALE events in PAD patients. Recently, the concept of dual pathway inhibition (low-dose rivaroxaban plus acetylic salicylic acid (ASA) has been tested in the COMPASS and VOYAGER-PAD trial. Compared to ASA alone dual pathway inhibition was superior to prevent MACE and MALE. After peripheral revascularization, in particular the risk for acute limb ischemia was reduced. In contrast, the risk for major bleeding is increased. Therefore, current guidelines recommend the combination of low-dose rivaroxaban and ASA in PAD patients with low bleeding risk. In patients with high bleeding risk, a single antiplatelet drug (preferable clopidogrel) is indicated. In patients with atherosclerotic vascular disease and indication for oral anticoagulation, no additional antiplatelet drug is necessary, as this would increase the risk of bleeding without improving the prognosis.ConclusionAntithrombotic treatment reduces MACE and MALE and is recommended in all patients with PAD. Individual bleeding risk should always be considered based on the current data situation and an individual benefit-risk assessment must be carried out.

Interpretable Machine Learning for the Prediction of Amputation Risk Following Lower Extremity Infrainguinal Endovascular Interventions for Peripheral Arterial Disease.

Severe peripheral artery disease (PAD) may result in lower extremity amputation or require multiple procedures to achieve limb salvage. Current prediction models for major amputation risk have had limited performance at the individual level. We developed an interpretable machine learning model that will allow clinicians to identify patients at risk of amputation and optimize treatment decisions for PAD patients. We utilized the American College of Surgeons National Surgical Quality Improvement Program database to collect preoperative clinical and laboratory information on 14,444 patients who underwent lower extremity endovascular procedures for PAD from 2011 to 2018. Using data from 2011 to 2017 for training and data from 2018 for testing, we developed a machine learning model to predict 30day amputation in this patient population. We present performance metrics overall and stratified by race, sex, and age. We also demonstrate model interpretability using Gini importance and SHapley Additive exPlanations. A random forest machine learning model achieved an area under the receiver-operator curve (AU-ROC) of 0.81. The most important features of the model were elective surgery designation, claudication, open wound/wound infection, white blood cell count, and albumin. The model performed equally well on white and non-white patients (Delong p-value = 0.189), males and females (Delong p-value = 0.572), and patients under age 65 and patients age 65 and older (Delong p-value = 0.704). We present a machine learning model that predicts 30day major amputation events in PAD patients undergoing lower extremity endovascular procedures. This model can optimize clinical decision-making for patients with PAD.

Artificial-Intelligence-Assisted Discovery of Genetic Factors for Precision Medicine of Antiplatelet Therapy in Diabetic Peripheral Artery Disease.

An increased risk of cardiovascular events was identified in patients with peripheral artery disease (PAD). Clopidogrel is one of the most widely used antiplatelet medications. However, there are heterogeneous outcomes when clopidogrel is used to prevent cardiovascular events in PAD patients. Here, we use an artificial intelligence (AI)-assisted methodology to identify genetic factors potentially involved in the clopidogrel-resistant mechanism, which is currently unclear. Several discoveries can be pinpointed. Firstly, a high proportion (>50%) of clopidogrel resistance was found among diabetic PAD patients in Taiwan. Interestingly, our result suggests that platelet function test-guided antiplatelet therapy appears to reduce the post-interventional occurrence of major adverse cerebrovascular and cardiac events in diabetic PAD patients. Secondly, AI-assisted genome-wide association study of a single-nucleotide polymorphism (SNP) database identified a SNP signature composed of 20 SNPs, which are mapped into 9 protein-coding genes (SLC37A2, IQSEC1, WASHC3, PSD3, BTBD7, GLIS3, PRDM11, LRBA1, and CNR1). Finally, analysis of the protein connectivity map revealed that LRBA, GLIS3, BTBD7, IQSEC1, and PSD3 appear to form a protein interaction network. Intriguingly, the genetic factors seem to pinpoint a pathway related to endocytosis and recycling of P2Y12 receptor, which is the drug target of clopidogrel. Our findings reveal that a combination of AI-assisted discovery of SNP signatures and clinical parameters has the potential to develop an ethnic-specific precision medicine for antiplatelet therapy in diabetic PAD patients.

Diabetes Mellitus and Its Impact on Patient-Profile and In-Hospital Outcomes in Peripheral Artery Disease.

Background: In patients with peripheral artery disease (PAD), the impact of diabetes mellitus (DM) on patient-profile and adverse in-hospital events is not well investigated. Methods: The German nationwide inpatient sample 2005–2019 was used for this analysis. Hospitalized PAD patients were stratified for DM and the influence of DM on patient-profile and adverse in-hospital events was investigated. Results: Our study comprised 2,654,871 hospitalizations (54.3% aged ≥70 years, 36.7% females) of patients with PAD in Germany 2005–2019. Among these, 864,691 (32.6%) patients had DM and 76,716 (2.9%) died during hospitalization. Diabetic PAD patients revealed an aggravated cardiovascular profile (Charlson Comorbidity Index: 6.0 (5.0–8.0) vs. 4.0 (3.0–5.0), p < 0.001). PAD patients with DM showed a higher rate of in-hospital mortality (3.5% vs. 2.6%, p < 0.001), as well as major adverse cardiovascular and cerebrovascular events (MACCE, 4.7% vs. 3.3%, p < 0.001) and had more often operated with amputation surgery (16.4% vs. 9.1%, p < 0.001). DM was an independent predictor of in-hospital mortality (OR 1.077 (95%CI 1.060–1.093), p < 0.001) and MACCE (OR 1.118 (95%CI 1.103–1.133), p < 0.001). In addition, amputations were also associated with DM (OR 1.804 (95%CI 1.790–1.818)), p < 0.001). Conclusions: DM is associated with an unfavorable clinical patient-profile and higher risk for adverse events in PAD patients, including substantially increased in-hospital mortality as well as MACCE rate, and were more often associated with amputation surgeries.

Serum ceramides and type 2 diabetes are mutually independent predictors of cardiovascular events in patients with peripheral artery disease

Abstract Introduction: Ceramides are enriched in atherosclerotic plaques, and a set of circulating ceramides including Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:1), and Cer(d18:1/24:0) has recently emerged as predictors of cardiovascular outcomes in coronary artery disease patients. Hypothesis: We hypothesize that they have the power to predict cardiovascular events in patients with peripheral artery disease (PAD). Methods: We measured the serum concentrations of the above mentioned ceramides in a cohort of 380 patients with sonographically proven PAD, of whom 107 had type 2 diabetes (T2DM). Prospectively, we recorded 221 cardiovascular events over a mean follow-up time of 6.3±2.3 years. Results: Cardiovascular event risk was higher in T2DM patients than in those who did not have diabetes (69 vs. 52%, p=0.001). The ceramides Cer(18:1/16:0) and Cer(18:1/24:1) and the respective ratios Cer(18:1/16:0) / Cer(18:1/24:0) and Cer(18:1/24:1) / Cer(18:1/24:0) were significant predictors of cardiovascular events both univariately and after multivariate adjustment including the presence of T2DM (figure). Conversely, T2DM predicted cardiovascular events independently from the investigated ceramides (adjusted HR 1.76 [1.31-2.35], p<0.001). Conclusions: We conclude that the investigated ceramides and T2DM are mutually independent predictors of cardiovascular events in PAD patients.

Abstract 17116: Incidence and Costs of Major Atherothrombotic Vascular Events Among Patients With Peripheral Artery Disease After Revascularization

Introduction: Peripheral artery disease (PAD), frequently requiring lower-extremity revascularization (LER), is associated with risk of major atherothrombotic vascular events (acute limb ischemia [ALI], major amputation of vascular etiology, myocardial infarction [MI], ischemic stroke [IS], cardiovascular [CV] death). Understanding the incidence and healthcare costs of such events in PAD patients post-revascularization may be important in translation. Methods: Patients with PAD who underwent LER were identified from Optum Clinformatics Data Mart claims database (Q1 2014 - Q2 2019). The first LER was considered index. Patients were required to be ≥50 years old at index with ≥6 months of prior health plan enrollment. Patients with IS, atrial fibrillation (AF), venous thromboembolism (VTE), intracranial hemorrhage, ESRD, or oral anticoagulant (OAC) use pre-index; or diagnoses of MI 30 days or ALI 14 days pre-index were excluded. Patients were followed until the earliest of 1) end of enrollment/data; 2) diagnosis of AF or VTE; or 3) OAC use. For each major vascular event, the incidence rate was assessed as the number of first events divided by patient-years of observation. Event-related healthcare costs per-patient-year (PPY) were also reported. Results: Of the 38,439 PAD patients meeting the study criteria, 6,675 (17.4%) had a major atherothrombotic vascular event over a median follow-up of 1.0 years (IQR: 0.4-2.1). The composite event incidence rate was 13.81 per 100 patient years [ALI: 5.51; lower-limb amputation: 5.15; MI: 3.19; IS: 2.06; CV-related death: 0.88]. PPY event-related costs ranged from $57,825 for IS to $108,302 for lower-limb amputation (Figure). Conclusions: One in six PAD patients have a major atherothrombotic vascular event within one year post-LER. Costs of these events are high, particularly for limb complications. Therefore, reducing the rate of such events could reduce the overall healthcare costs for this population.

Association of gout with major adverse cardiovascular events and all-cause mortality in patients with peripheral artery disease

Background and aimsPrior epidemiological studies have suggested that individuals with gout are at greater risk of cardiovascular events, but there have been no studies in people with peripheral artery disease (PAD). The aim of this study was to investigate the relationship between gout and major adverse cardiovascular events (MACE) and all-cause mortality in people with PAD. MethodsParticipants with a range of PAD presentations, including carotid artery disease, aortic or peripheral aneurysm and lower limb PAD, were prospectively recruited from outpatient vascular departments within Australia. MACE (myocardial infarction, stroke or cardiovascular death) and all-cause mortality were identified through out-patient follow-up and linked medical records. Propensity-score matching was undertaken to generate a matched cohort of patients with and without a history of gout. Kaplan-Meier survival analysis and Cox-proportional hazard analysis were used to examine the association of gout with MACE and all-cause mortality. ResultsA total of 4308 people with PAD, of whom 334 had a history of gout, were included and followed for a median (inter-quartile range) of 2.1 (0.1–5.9) years. In the unadjusted analyses, participants with gout were at increased risk of MACE (hazard ratio, HR 1.37, 95% confidence intervals, CI 1.09–1.71, p = 0.006) and all-cause mortality (HR 1.38, 95% 1.13–1.68, p = 0.002), however, the associations were lost in the adjusted analyses. In the propensity-score matched cohort, gout was not significantly associated with an increased risk for MACE or all-cause mortality. ConclusionsGout was not independently associated with increased cardiovascular events in PAD patients.

Peripheral Artery Disease Patients With Chronic Limb-Threatening Ischemia Show Altered Blood Microbiota Composition as Compared with Intermittent Claudication

Chronic limb-threatening ischemia (CLTI) is a severe manifestation of peripheral artery disease (PAD) with high morbidity for aging populations. While metabolites produced by the intestinal microbiota have been shown to predict long-term risk of adverse events in PAD patients, the contribution of the blood microbiota to the development of CLTI has not been investigated. We sought to profile the blood microbiota of PAD patients with CLTI as compared with intermittent claudication (CLAUD) to identify differences in microbial composition.

P1956Geriatric nutritional risk index as predictor for long-term survival and cardiovascular or limb events in peripheral arterial disease patients

Abstract Background The geriatric nutritional risk index (GNRI) is a simple tool to assess the nutritional risk and associated with mortality. However, there are no reports focusing GNRI in peripheral artery disease (PAD) patients. Purpose The purpose of this study was to examine the effects of GNRI for long-term survival, cardiovascular and limb events in PAD patients. Methods A prospective cohort study was performed in 1219 PAD patients. Baseline GNRI was calculated from serum albumin level and body-mass-index. The patients were divided into four groups by GNRI level (G1: &gt;98; G2: 92–98; G3: 82–91; G4: &lt;82). The endpoints were overall survival (OS) and freedom from major adverse cardiovascular and limb events (MACE and MACLE). Results The median follow-up was 73 months. There were 626 deaths (51.4%) during follow-up. The rate of cardiovascular death among dead was 51.3%. The OS rates markedly depended on GNRI level (p&lt;0.01). The 5-year OS rates were G1: 80.8%, G2: 62.0%, G3: 40.0%, G4: 23.3%, respectively. In multivariate analyses, GNRI, age, low ankle brachial pressure index (ABI), low estimated glomerular filtration rate (eGFR), and high C-reactive protein (CRP) levels were independent factors associated with OS (&lt;0.05). GNRI, age, low ABI, diabetes mellitus, coronary artery disease, lower eGFR and higher CRP levels were associated with MACE and MACLE (p&lt;0.05, respectively). Besides, statins improved OS, MACE, and MACLE (&lt;0.01, respectively). Conclusions GNRI was an independent predictor for OS, MACE, and MACLE in PAD patients. Furthermore,statins improved OS, MACE and MACLE in patients with PAD.

P4497Serum ceramides and type 2 diabetes are mutually independent predictors of cardiovascular events in patients with peripheral artery disease

Abstract Background Ceramides are enriched in atherosclerotic plaques, and a set of circulating ceramides including Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:1), and Cer(d18:1/24:0) has recently emerged as predictors of cardiovascular outcomes in coronary artery disease patients. Purpose The purpose of this study was to investigate their power to predict cardiovascular events in patients with peripheral artery disease (PAD). Methods We measured the serum concentrations of the above mentioned ceramides in a cohort of 380 patients with sonographically proven PAD, of whom 107 had type 2 diabetes (T2DM). Prospectively, we recorded 221 cardiovascular events over a mean follow-up time of 6.3±2.3 years. Results Cardiovascular event risk was higher in T2DM patients than in those who did not have diabetes (69 vs. 52%, p=0.001). The ceramides Cer(18:1/16:0) and Cer(18:1/24:1) and the respective ratios Cer(18:1/16:0) / Cer(18:1/24:0) and Cer(18:1/24:1) / Cer(18:1/24:0) were significant predictors of cardiovascular events both univariately and after multivariate adjustment including the presence of T2DM (figure). Conversely, T2DM predicted cardiovascular events independently from the investigated ceramides (adjusted HR 1.76 [1.31–2.35], p&lt;0.001). Conclusion We conclude that the investigated ceramides and T2DM are mutually independent predictors of cardiovascular events in PAD patients.

433-P: Serum Ceramides and Type 2 Diabetes Are Mutually Independent Predictors of Cardiovascular Events in Patients with Peripheral Artery Disease

Ceramides are enriched in atherosclerotic plaques, and a set of circulating ceramides including Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:1), and Cer(d18:1/24:0) has recently emerged as predictors of cardiovascular outcomes in coronary artery disease patients. However, their power to predict cardiovascular events in patients with peripheral artery disease (PAD) is unknown and is addressed in the present study. We measured the serum concentrations of the above mentioned ceramides in a cohort of 380 patients with sonographically proven PAD, of whom 107 had type 2 diabetes (T2DM). Prospectively, we recorded 221 cardiovascular events over a mean follow-up time of 6.3±2.3 years. Cardiovascular event risk was higher in T2DM patients than in those who did not have diabetes (69 vs. 52%, p=0.001). The ceramides Cer(18:1/16:0) and Cer(18:1/24:1) and the respective ratios Cer(18:1/16:0)/Cer(18:1/24:0) and Cer(18:1/24:1)/Cer(18:1/24:0) were significant predictors of cardiovascular events both univariately and after multivariate adjustment including the presence of T2DM (Figure). Conversely, T2DM predicted cardiovascular events independently from the investigated ceramides (adjusted HR 1.76 [1.31-2.35], p&amp;lt;0.001). We conclude that the investigated ceramides and T2DM are mutually independent predictors of cardiovascular events in PAD patients. Disclosure A. Leiherer: None. A. Muendlein: None. C.H. Saely: None. R. Laaksonen: None. M. Laaperi: None. A. Vonbank: None. B. Larcher: None. A. Mader: None. P. Fraunberger: None. I. Baumgartner: None. H. Drexel: None. J.F. Dopheide: None.

Carotid Artery Reactivity Predicts Events in Peripheral Arterial Disease Patients.

Patients with peripheral arterial disease (PAD) have increased risk on future cerebro- and cardiovascular events. Our aim was to examine whether carotid artery reactivity (CAR; a novel, simple procedure to examine endothelial function) predicts cardiovascular events in PAD patients. Increased risk for future cardiovascular events in PAD patients is likely related to endothelial dysfunction, highlighting the necessity for simple assessment of endothelial function. A total of 172 PAD patients (68 ± 10 years, 67% male) underwent the CAR, which involves ultrasound measurement of carotid artery diameter during sympathetic stimulation produced by 90-second hand immersion in 4°C ice-water (ie, cold pressor test). CAR-responses were dichotomized into carotid constriction or dilation. We recorded cardiac and cerebrovascular events, mortality, and clinical progression to percutaneous transluminal angioplasty or loss of patency during 12-month follow-up. Eighty-two PAD patients demonstrated carotid constriction and 90 patients demonstrated dilation. PAD patients with carotid constriction showed more cardiovascular events compared to patients with dilation (Kaplan-Meier Log rank; P < 0.05). Cox proportional hazard models showed that patients with carotid constriction continued to show higher risk for cardiovascular events [hazard ratio: 4.1; 95% confidence interval (CI), 1.3-12.5] and clinical progression (hazard ratio: 2.0; 95% CI, 1.2-3.3), even after adjustment for other risk factors. Ankle brachial pressure index and carotid intima-medial thickness alone did not predict (cardiovascular) event or improve risk assessment beyond that provided by CAR. Carotid vasoconstriction identifies PAD patients with a 4-fold increased risk for future cardiovascular events and 2-fold increased risk for clinical deterioration. CAR provides a simple, novel strategy to predict cardiovascular events and progression in PAD patients. www.trialregister.nl/trialreg/index.asp, NTR-4117.

Metformin Is Associated with Improved Survival and Decreased Cardiac Events with No Impact on Patency and Limb Salvage after Revascularization for Peripheral Arterial Disease

The incidence of cardiovascular and limb-specific adverse outcomes is higher in peripheral arterial disease (PAD) patients with diabetes. Metformin is associated with improved cardiovascular morbidity and mortality. However, the effect of metformin on limb-specific outcomes is unclear. The objective of this study was to assess the effect of metformin on outcomes after intervention for PAD. Patients who underwent revascularization for chronic limb ischemia (Rutherford 3-6) between June 2001 and December 2014 were retrospectively identified. Primary patency (PP), secondary patency (SP), limb salvage (LS), major adverse limb events (MALE), major adverse cardiac events (MACE), and survival rates were compared using Kaplan-Meier and Cox regression. One thousand sixty-four limbs in 1204 patients were identified (147 metformin, 196 other hypoglycemics [OH], 216 insulin, and 645 nondiabetics (nondiabetes mellitus [DM]). Non-DM had significantly lower incidence of CAD (46%) than insulin (65%), metformin (56%), and OH groups (63%) (P<0.001). Insulin patients (17%) had significantly higher incidence of end-stage renal disease (ESRD) than non-DM (3%), metformin (1.4%), and OH groups (8%) (P<0.001). Ninety four percent of patients in the metformin group were on aspirin, which was significantly higher than non-DM (86%), OH (83%), and insulin groups (86%) (P=0.02). Similarly, statin use was significantly higher in the metformin group (71%) than in OH (64%), insulin (61%), and non-DM groups (55%) (P=0.002). Majority of patients in the insulin group presented with critical limb ischemia (CLI) (93%), which was significantly greater than the metformin (59%), OH (72%), and non-DM groups (50%) (P<0.001). Sixty-month PP was significantly greater in non-DM group (62%) (P=0.005) in overall comparison with no significant difference between metformin (56%), OH (60%), and insulin (51%) groups (P=0.06). Sixty-month SP was similar in metformin (76%), OH (85%), insulin (76%), and non-DM (80%) groups (P=0.27). LS was significantly worse in insulin group (62%) (P<0.001) with no significant difference between metformin (84%), OH (83%), and non-DM (87%) groups (P=0.45). Freedom from MALE at 60 months was 53% in the insulin group, which was significantly worse as compared with metformin (71%), OH (70%), and non-DM (67%) groups (P=0.001). Sixty-month survival was significantly improved in metformin (60%) and non-DM (60%) groups as compared with that in OH (41%) and insulin groups (30%) (P<0.001). Freedom from MACE was significantly greater in metformin (44%) and non-DM (52%) groups than that in OH (37%) and insulin groups (25%) (P<0.001). Metformin use (HR, 0.7 [0.5-0.9]; P=0.008) was an independent factor associated with freedom from mortality. Metformin is associated with improved survival and decreased incidence of adverse cardiac events in PAD patients. However, it did not have an impact on patency or LS rates after open and endovascular interventions. LS was worse in diabetic patients primarily treated with insulin.

Systematic Review and Meta-Analysis of the Association Between C-Reactive Protein and Major Cardiovascular Events in Patients with Peripheral Artery Disease

Patients with peripheral artery disease (PAD) are at substantial risk of cardiovascular events. There is interest in using blood markers, such as C-reactive protein (CRP), to monitor prognosis and treatment efficacy in PAD patients. The aim of this meta-analysis was to assess the association between CRP and major cardiovascular events in PAD patients. Studies evaluating the association between CRP and major cardiovascular events (myocardial infarction, stroke, cardiac revascularisation and mortality) were identified using MEDLINE and the Cochrane library. Studies that did not include participants with PAD, measure CRP, or follow-up patients for cardiovascular events were excluded. Meta-analyses of published adjusted hazard ratios (HR) were conducted using an inverse variance-weighted random effects model, and heterogeneity was assessed with the I2 index. A total of 16 studies involving 5041 participants met the inclusion criteria for the systematic review. Eight studies were included in the meta-analyses. Summary effect estimates were reported as HR comparing higher and lower quantiles, and HR per unit increase in logeCRP. PAD patients with higher CRP had a significantly greater risk of major cardiovascular events compared with those with lower CRP (HR 2.26, 95% CI 1.65–3.09, P < 0.001). The HR for major cardiovascular events was 1.38 (95% CI 1.16–1.63, P < 0.001) per unit increase in logeCRP. The present findings suggest that high circulating CRP is predictive of major cardiovascular events in PAD patients.

Baseline Characterization of Japanese Peripheral Arterial Disease Patients - Analysis of Surveillance of Cardiovascular Events in Antiplatelet-Treated Arteriosclerosis Obliterans Patients in Japan (SEASON).

Despite mounting evidence of increased cardiovascular events in patients with peripheral arterial disease (PAD), the overall incidence of cardiovascular events in PAD patients has not been fully clarified in Japan. The prospective Surveillance of cardiovascular Events in Antiplatelet-treated arterioSclerosis Obliterans patients in JapaN (SEASON) is a prospective observational multicenter study and here we report the baseline clinical characteristics, including atherosclerosis risk factor prevalence, in PAD patients treated with antiplatelet agents. The SEASON registry enrolled 11,375 patients in 1,745 institutions and the data for 10,322 patients were analyzed. At baseline, the average age was 73.8±9.9 years, 60.0% were male and 83.9% were in Fontaine stage I or II. They had arteriosclerosis risk factors, such as current smoking (16.2%), hypertension (61.5%), diabetes mellitus (38.3%) and dyslipidemia (38.8%). There were complications including heart disease (29.7%), cerebrovascular disease (17.1%) and chronic kidney disease (14.3%). A subpopulation analysis revealed that the proportions of patients with risk factors were high in patients with lower ankle-brachial pressure index value. The baseline characteristics of the SEASON population demonstrate that real-world PAD patients have cardiovascular risk factors and comorbidities next to definite PAD patients. Further analysis of this database will contribute to understanding the real-world situation of PAD patients receiving antiplatelet therapy in Japan. (Circ J 2016; 80: 712-721).

Abstract 12428: Efficacy of a Risk Reduction Program to Improve Cardiovascular Outcomes in Patients With Peripheral Arterial Disease: A Propensity Score-Matched Study

Introduction: Patients with peripheral arterial disease (PAD) are often undertreated for cardiovascular (CV) risk factors, and they are at high risk for CV events. Hypothesis: A program that focuses on guideline-based risk factor management reduces adverse CV and limb events in PAD patients. Methods: A propensity-score matched observational cohort study with up to 7 years of follow-up was conducted using administrative databases in Ontario, Canada. Symptomatic PAD patients that were enrolled in the Systematic Assessment of Vascular Risk (SAVR) program between July 2004 and April 2007 were matched with up to 2 (control) patients with PAD from other Ontario tertiary vascular centers not enrolled in the program. The primary outcome was a composite of death, stroke or myocardial infarction (MI). Secondary outcomes included lower limb amputation and revascularization procedures. Cox proportional hazards regression analysis was used to compare outcomes between the groups. Results: A total of 791 patients were studied. During follow-up, the SAVR group (n=290) experienced the primary outcome at a significantly lower rate than the control group (adjusted HR, 0.64 [95% CI, 0.52 to 0.78]; P&lt;0.001) (Figure). SAVR patients were also less likely to undergo major amputation (adjusted HR, 0.47 [95% CI, 0.29 to 0.77]; P=0.002), minor amputation (adjusted HR, 0.26 [95% CI, 0.13 to 0.54]; P&lt;0.001), arterial bypass surgery (adjusted HR, 0.47 [95% CI, 0.30 to 0.73]; P&lt;0.001), and less likely to have a hospitalization due to heart failure (adjusted HR, 0.73 [95% CI, 0.53 to 0.998]; P=0.048). The rate of peripheral angioplasty was higher among the SAVR group (adjusted HR, 3.0 [95% CI, 2.2 to 4.1]; P&lt;0.001). Conclusions: A multifactor risk reduction program targeted to patients with PAD is associated with fewer adverse CV and limb events over the long-term. Greater focus is needed on developing structured programs for risk factor control in these high-risk patients.

Do the Effects of Secondary Prevention of Cardiovascular Events in PAD Patients Differ from Other Atherosclerotic Disease?

Atherosclerosis is considered a generalized disease. Similar or identical etiopathogenetic mechanisms and risk factors are involved in various atherosclerotic diseases, and the positive effects of preventive measures on atherogenesis in different parts of the arterial system were shown. However, until know, great emphasis has been placed on the aggressive pharmacological management of coronary artery disease (CHD), while less attention has been devoted to the management of peripheral arterial disease (PAD), despite its significant morbidity and mortality. Data on the efficacy of preventive measures in PAD patients have mostly been gained from subgroup analyses from studies devoted primarily to the management of coronary patients. These data have shown that treatment of risk factors for atherosclerosis with drugs can reduce cardiovascular events also in patients with PAD. The effects of some preventive procedures in PAD patients differ from coronary patients. Aspirin as a basic antiplatelet drug has been shown to be less effective in PAD patients than in coronary patients. The latest Antithrombotic Trialists’ Collaboration (ATC) meta-analysis demonstrates no benefit of aspirin in reducing cardiovascular events in PAD. Statins reduce cardiovascular events in all three of the most frequently presented cardiovascular diseases, including PAD to a comparable extent. Recent studies indicate that in PAD patients, in addition to a reduction in cardiovascular events, statins may have some hemodynamic effects. They prolong walking distance and improve quality of life. Similarly, angiotensin enzyme inhibitors are also effective in the prevention of cardiovascular events in coronary, cerebrovascular, as well as PAD patients and show positive effects on the walking capacity of patients with intermittent claudication. In PAD patients, the treatment of hypertension and diabetes also effectively prevents cardiovascular morbidity and mortality. As PAD patients are at a highest risk of cardiovascular complications, the risk factors of atherosclerosis should be treated intensively in this group of patients. Most of the preventive measures, including the drugs used for prevention of CHD, are also effective in PAD patients.

Amino-Terminal Pro-B-Type Natriuretic Peptide and High-Sensitivity C-Reactive Protein but Not Cystatin C Predict Cardiovascular Events in Male Patients with Peripheral Artery Disease Independently of Ambulatory Pulse Pressure

Patients with peripheral arterial disease (PAD) are at high risk for cardiovascular (CV) events. We have previously shown that ambulatory pulse pressure (APP) predicts CV events in PAD patients. The biomarkers amino-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein (hs-CRP), and cystatin C are related to a worse outcome in patients with CV disease, but their predictive values have not been studied in relation to APP. Blood samples and 24-hour measurements of ambulatory blood pressure were examined in 98 men referred for PAD evaluation during 1998-2001. Patients were followed for a median of 71 months. The outcome variable was CV events defined as either CV mortality or any hospitalization for myocardial infarction, stroke, or coronary revascularization. The predictive values of log(NT-proBNP), log(hs-CRP), and log(cystatin C) alone and together with APP were assessed by multivariable Cox regression. Area under the curve (AUC) and net reclassification improvement (NRI) were calculated compared with a model containing other significant risk factors. During follow-up, 36 patients had at least 1 CV event. APP, log(NT-proBNP), and log(hs-CRP) all predicted CV events in univariable analysis, whereas log(cystatin C) did not. In multivariable analysis log(NT-proBNP) (hazard ratio (HR) = 1.62; 95% confidence interval (CI) = 1.05-2.51) and log(hs-CRP) (HR = 1.63; 95% CI = 1.19-2.24) predicted events independently of 24-hour PP. The combination of log(NT-proBNP), log(hs-CRP), and average day PP improved risk discrimination (AUC = 0.833 vs. 0.736; P < 0.05) and NRI (37%; P < 0.01) when added to other significant risk factors. NT-proBNP and hs-CRP predict CV events independently of APP and the combination of hs-CRP, NT-proBNP, and day PP improves risk discrimination in PAD patients.