Therapy For Peripheral Arterial Disease Research Articles

CYP2C19 genotype-guided antithrombotic treatment versus conventional clopidogrel therapy in peripheral arterial disease: study design of a randomized controlled trial (GENPAD)

Clopidogrel is recommended in international guidelines to prevent arterial thrombotic events in patients with peripheral arterial disease (PAD). Clopidogrel itself is inactive and metabolism is dependent on the CYP2C19 enzyme. About 30% of Caucasian PAD patients receiving clopidogrel carry 1 or 2 CYP2C19 loss-of-function allele(s) and do not or to a limited extent convert the prodrug into its active metabolite. As a result, platelet inhibition may be inadequate which could lead to an increased risk of adverse clinical events related to arterial thrombosis. A CYP2C19 genotype-guided antithrombotic treatment might be beneficial for PAD patients. GENPAD is a multicenter randomized controlled trial involving 2,276 PAD patients with an indication for clopidogrel monotherapy. Patients with a separate indication for dual antiplatelet therapy or stronger antithrombotic therapy are not eligible for study participation. Patients randomized to the control group will receive clopidogrel 75 mg once daily without pharmacogenetic guidance. Patients randomized to the intervention group will be tested for carriage of CYP2C19 *2 and *3 loss-of-function alleles, followed by a genotype-guided antithrombotic treatment with either clopidogrel 75 mg once daily for normal metabolizers, clopidogrel 150 mg once daily for intermediate metabolizers, or acetylsalicylic acid 80 mg once daily plus rivaroxaban 2.5 mg twice daily for poor metabolizers. The primary outcome is a composite of myocardial infarction, ischemic stroke, cardiovascular death, acute or chronic limb ischemia, peripheral vascular interventions, or death. The secondary outcomes are the individual elements of the primary composite outcome and clinically relevant bleeding complications. The aim of the GENPAD study is to evaluate the efficacy, safety, and cost-effectiveness of a genotype-guided antithrombotic treatment strategy compared to conventional clopidogrel treatment in PAD patients.

Role of Lipid-Lowering Therapy in Peripheral Artery Disease.

Atherosclerosis is a multifactorial, lipoprotein-driven condition that leads to plaque formation within the arterial tree, leading to subsequent arterial stenosis and thrombosis that accounts for a large burden of cardiovascular morbidity and mortality globally. Atherosclerosis of the lower extremities is called peripheral artery disease and is a major cause of loss in mobility, amputation, and critical limb ischemia. Peripheral artery disease is a common condition with a gamut of clinical manifestations that affects an estimated 10 million people in the United States of America and 200 million people worldwide. The role of apolipoprotein B-containing lipoproteins, such as LDL and remnant lipoproteins in the development and progression of atherosclerosis, is well-established. The focus of this paper is to review existing data on lipid-lowering therapies in lower extremity atherosclerotic peripheral artery disease.

Vascular Pathology and Impact of Stent Eccentricity for Stent Restenosis in Femoropopliteal Endovascular Therapy

PurposeTo explore the clinical features associated with stent eccentricity and reveal the impact of stent eccentricity on the risk of 1-year restenosis after femoropopliteal stent implantation for symptomatic atherosclerotic peripheral artery disease (PAD). Materials and MethodsThe clinical database of a multicenter prospective study was used. It registered 2,018 limbs of 1,766 patients in whom intravascular ultrasound (IVUS)-supported femoropopliteal endovascular therapy (EVT) for symptomatic atherosclerotic PAD was planned from November 2015 to June 2017. The study included 1,233 limbs of 1,088 patients implanted with a bare nitinol stent, drug-eluting stent (DES), or stent graft and administered ≥2 antithrombotic drugs. The stent eccentricity was evaluated using IVUS, calculated as [(maximum diameter) / (minimum diameter) − 1] at the cross-sectional segment with the lowest lumen area after stent implantation. ResultsChronic total occlusion and bilateral arterial calcification (peripheral artery calcification scoring system Grades 3 and 4) were positively associated with stent eccentricity, whereas renal failure while receiving dialysis, DES use, and stent graft use were negatively associated with stent eccentricity (all P < .05). Stent eccentricity was associated with an increased risk of 1-year restenosis (odds ratio [OR], 1.18; 95% CI, 1.01–1.37; P = .034). However, after adjustment for lesion severity and implanted stent types, the association was no longer significant (OR, 1.07; 95% CI, 0.91–1.24; P = .43). ConclusionsStent eccentricity was not significantly associated with the risk of 1-year restenosis after femoropopliteal EVT.

Abstract 267: Altered Macrophage Response Associated With Impaired Skeletal Muscle Regeneration In Murine Model Of Limb Ischemia

Introduction: Skeletal muscle regeneration in the ischemic limb is a complex complex process dependent on coordinated intercellular communication involving an array of cell types. These interactions are not well understood, and the development of novel regenerative therapies for peripheral arterial disease will require new insight into the cellular heterogeneity and intercellular signaling that occurs in the ischemic limb. Macrophages play a role in orchestrating critical events in muscle regeneration; hence we sought to characterize their transcriptional signature and identify candidate signaling pathways in the context of limb ischemia. Methods: We applied single-cell RNA sequencing (scRNA-seq) to skeletal muscle obtained from regenerative (C57BL/6) and non-regenerative (BALB/c) mouse limbs at multiple time points following ligation of the femoral artery. We used CellChat, a computation tool, to predict signaling pathway activity between macrophages and muscle satellite cells (MuSC) based on our single-cell data. Results: We identified 12 distinct macrophage populations in the regenerative and non-regenerative limb, including strain-specific macrophage clusters associated with the response to ischemia. Regenerative macrophages displayed a proliferative phenotype, while non-regenerative macrophages exhibited a persistent pro-inflammatory phenotype. Additionally, we identified several candidate signaling interactions between specific macrophage clusters and MuSCs. Notable potential interactions included enhanced FN1 to SDC4 and THBS1 to SDC4 signaling between regenerative macrophage and MuSCs, as well as OPN to CD44 signaling between non-regenerative macrophages and MuSCs. Conclusions: Our study maps the dynamic macrophage response in the ischemic limb at single-cell resolution. This provides a valuable resource to investigate macrophage-mediated mechanisms of skeletal muscle regeneration in response to limb ischemia.

Malnutrition is Associated with Increased Morbidity and Death in Dialysis Patients Undergoing Endovascular Therapy for Peripheral Artery Disease

Revascularisation for peripheral artery disease (PAD) is increasingly common in dialysis patients. Patients with PAD who have undergone revascularisation are at high risk of subsequent complications. Malnutrition is an important modifiable risk factor for dialysis patients, yet few data exist on the prognostic impact of malnutrition on post-procedure long term outcomes. The objective was to assess the prevalence and prognostic association of malnutrition using the Controlling Nutritional Status (CONUT) score in a prospective cohort of dialysis patients undergoing endovascular therapy (EVT) for PAD. A total of 395 consecutive dialysis patients undergoing endovascular revascularisation for lower extremity PAD between 2005 and 2019 were examined for the primary outcome of all cause death. Secondary outcomes included major adverse limb events (MALEs), defined as acute limb ischaemia, major amputation, and clinically driven revascularisation; and major adverse cardiovascular events (MACEs). Nutritional status was assessed by CONUT score, a screening tool for malnutrition, incorporating albumin, cholesterol, and total lymphocyte count. According to the CONUT score, 40.8% of patients were moderately or severely malnourished. During a median follow up of 2.2 years, 218 (55.2%) patients died; 211 (53.4%) patients had MALEs, and MACEs occurred in 135 (34.2%) patients. Compared with normal nutritional status, severe malnutrition was associated with a significantly increased risk of all cause death (adjusted hazard ration [aHR] 4.83, 95% confidence interval [CI] 2.56 - 9.12) and MALEs (aHR 2.42, 95% CI 1.23 - 4.74) but not MACEs (aHR 1.81, 95% CI 0.74 - 4.40). Similar results were observed when the CONUT score was analysed as a continuous variable. Malnutrition is common in dialysis patients with PAD requiring endovascular therapy and is strongly associated with increased death and MALEs. Clinical trials are needed to evaluate whether nutritional interventions improve outcomes for dialysis patients after peripheral revascularisation.

Intensive exercise therapy for restenosis after superficial femoral artery stenting: the REASON randomized clinical trial

Endovascular treatment (EVT) is the main treatment for peripheral artery disease (PAD). Despite advances in device development, the restenosis rate remains high in patients with femoropopliteal lesions (FP). This study aimed to evaluate the effectiveness of exercise training in reducing the 1-year in-stent restenosis rate of bare metal nitinol stents for FPs. This prospective, randomized, open-label, multicenter study was conducted from January 2017 to March 2019. We randomized 44 patients who had claudication with de novo stenosis or occlusion of the FP into an intensive exercise group (n = 22) and non-intensive exercise group (n = 22). Non-intensive exercise was defined as walking for less than 30 min per session, fewer than three times a week. We assessed exercise tolerance using an activity meter at 1, 3, 6, and 12 months, and physiotherapists ensured maintenance of exercise quality every month. The primary endpoint was instant restenosis defined as a peak systolic velocity ratio > 2.5 on duplex ultrasound imaging. Kaplan–Meier analysis was used to evaluate the data. There were no significant differences in background characteristics between the groups. Six patients dropped out of the study within 1 year. In terms of the primary endpoint, intensive exercise significantly improved the patency rate of bare nitinol stents at 12 months. The 1-year freedom from in-stent restenosis rates were 81.3% in the intensive exercise group and 47.6% in the non-intensive exercise group (p = 0.043). No cases of stent fracture were observed in the intensive exercise group. Intensive exercise is safe and reduces in-stent restenosis in FP lesions after endovascular therapy for PAD. Clinical trial registration: University Hospital Medical Information Network Clinical Trials Registry (No. UMIN 000025259).

Current and Novel Emerging Medical Therapies for Peripheral Artery Disease: A Literature Review.

Despite the improvements in endovascular techniques during the last decades, there is still an increase in the prevalence of peripheral artery disease (PAD) with limited practical treatment, which timeline impact of any intervention for critical limb ischemia (CLI) is poor. Most common treatments are not suitable for many patients due to their underlying diseases, including aging and diabetes. On the one hand, there are limitations for current therapies due to the contraindications of some individuals, and on the other hand, there are many side effects caused by common medications, for instance, anticoagulants. Therefore, novel treatment strategies like regenerative medicine, cell-based therapies, Nano-therapy, gene therapy, and targeted therapy, besides other traditional drugs combination therapy for PAD, are newly considered promising therapy. Genetic material encoding for specific proteins concludes with a potential future for developed treatments. Novel approaches for therapeutic angiogenesis directly used the angiogenetic factors originating from key biomolecules such as genes, proteins, or cell-based therapy to induce blood vessel formation in adult tissues to initiate the recovery process in the ischemic limb. As PAD is associated with high mortality and morbidity of patients causing disability, considering the limited treatment choices for these patients, developing new treatment strategies to prevent PAD progression and extending life expectancy, and preventing threatening complications is urgently needed. This review aims to introduce the current and the novel strategies for PAD treatment that lead to new challenges for relief the patient's suffered from the disorder.

Exercise therapy for peripheral artery disease in 2022: Progress and a prediction

Exercise therapy for peripheral artery disease in 2022: Progress and a prediction

Changes to Drug-Coated Balloon Reimbursement Affect Peripheral Arterial Disease Patient Care: A Single-Center Experience.

Introduction: Balloon angioplasty (BA) and stenting have long been the mainstays of endovascular therapy in peripheral arterial disease (PAD). However, the rise of drug-coated balloons (DCBs) has revolutionized care in recent years, with multiple clinical trials showing superiority over BA in maintaining primary patency and freedom from target lesion revascularization (TLR). With the recent drop of the add-on payment for DCBs, a barrier for their use and consequently reduced therapy adoption in PAD might arise. We assessed if this affected physicians' behavior and hospital administration towards stocking and using DCBs.Methods: This single-center, retrospective study evaluated DCB utilization in 2017 versus 2018. Data were collected in two groups: 1) July 1, 2017, to December 31, 2017 - with pass-through code (PTC) - prior medical billing reimbursement - and 2) January 1, 2018, to June 30, 2018 - without PTC - markedly reduced reimbursement. Patients treated for superficial femoral artery (SFA) or popliteal artery (POP) disease were included. The study aimed to determine changes in DCB utilization between the years with and without PTC, and we investigated the treatments that have replaced DCBs. Additionally, we aimed to collect data on readmissions and procedure costs compared to national data.Results: From July through December 2017, 350 DCBs were used in 209 patients (1.675 DCBs per patient), while from January through June 2018, 256 DCBs were used in 180 patients (1.422 DCBs per patient) - a 15.07% reduction in DCBs per patient. The detailed numbers of DCB-treated patients were presented as fractions of total interventions in the groups with and without PTC.Conclusion: The findings of this study show a statistically significant reduction in DCB usage following PTC withdrawal. There are several ethical implications to these findings, primarily highlighting patient beneficence and justice. Moving forward, it will be important to determine if this shift in treatment is owed to other treatment strategies such as BA, BA and atherectomy, BA and bare-metal stents (BMS), or BA and drug-eluting-stents (DES). The next steps should also include determining procedure costs and comparing readmission rates.

Method to Improve Administered Cells Via Intramuscular Route to Augment Efficacy of Regenerative Cell Therapy in The Field of Peripheral Artery Disease

In the field of peripheral artery disease (PAD), regenerative cell therapy has been expected to be a new alternative therapy especially for severely diseased patients. Although various preclinical studies showed promising results, those therapies failed to show sufficient efficacy for actual PAD patients and current guideline do not recommend regenerative therapy for PAD. The disappointing result may be caused by low retention rate of administered substance. Recently we published an article regarding novel method to augment the effect of cell therapy. In this review article, we would like to focus on the importance of improvement in cell survival and prerequisite factors to develop effective regenerative therapy for PAD patients.

Analysis of the relationship between sex and prescriptions for guideline-recommended therapy in peripheral arterial disease, in relation to 1-year all-cause mortality: a primary care cohort study

ObjectivesTo explore population patterns of sex-based incidence and prevalence of peripheral arterial disease (PAD), guideline-directed best medical therapy prescriptions and its relationship with all-cause mortality at 1 year.DesignA retrospective cohort...

Gender Differences in Outpatient Peripheral Artery Disease Management in Germany: A Population Based Study 2009–2018

Peripheral artery disease (PAD) is a major risk factor for morbidity and death. Despite clear guideline recommendations regarding outpatient treatment and pharmacotherapy, implementation is inadequate. Gender differences are becoming increasingly important, especially in patients with atherosclerosis. Gender stratified PAD prevalence and differences in treatment by specialised outpatient care and pharmacotherapy were analysed in 70.1 million statutorily insured patients/year in Germany between 2009 and 2018. This was based on claims data according to §295 of the social code (SGB V) and drug prescription data according to §300 SGB V. Diagnosis of PAD was defined according to ICD I70.2-9 coding. Statistical analysis was performed with the chi square test for trend and two way ANOVA. In total, 17 633 970 patients with PAD were identified, of whom 47% were female. Prevalence of PAD in Germany increased between 2009 and 2018 and was higher in male patients. Only a minority of 37.1% presented to a vascular specialist. Interestingly, female patients were both less likely to present to a vascular specialist and to receive guideline recommended pharmacotherapy. Overall prescription rates of statins and antiplatelet drugs increased between 2009 and 2018, however. PAD stages were stratified by intermittent claudication (IC) and chronic limb threatening ischaemia (CLTI). In CLTI even fewer patients received a statin, with the gender gap increasing. The results demonstrate gender based differences in pharmacotherapy and specialised outpatient care of patients with PAD. While overall outpatient treatment by vascular specialists and guideline recommended medical therapy of PAD are low, women and patients with CLTI remain undertreated.

Novel Self-expanding Shape-Memory Bioresorbable Peripheral Stent Displays Efficient Delivery, Accelerated Resorption, and Low Luminal Loss in a Porcine Model

Objective and Design: The search for improved stenting technologies to treat peripheral artery disease is trending toward biodegradable self-expanding shape-memory stents that, as of now, still suffer from the acute trade-off between deliverability and luminal stability: Higher deliverability leads to lower lumen stability, vessel recoil, and stent breakage. This study was aimed at the development and testing of a self-expanding bioresorbable poly(l,l-lactide-co-ε-caprolactone) stent that was designed to produce confident self-expansion after efficient crimping, as well as quick bioresorption, and sufficient radial force. Materials and Methods: Bench tests were employed to measure shape-memory properties, radial force, and hydrolytic degradation of the stent. The porcine model was employed to study deliverability, lumen stability, biocompatibility, and stent integrity. A total of 32 stents were implanted in the iliac arteries of 16 pigs with 15 to 180 day follow-up periods. The stented vessels were studied by angiography and histological evaluation. Results: Recovery of the diameter of the stent due to shape-memory effect was equal to 90.6% after 6Fr crimping and storage in refrigeration for 1 week. Radial force measured after storage was equal to 0.7 N/mm. Technical success of implantation in pigs (after the delivery implemented by pusher) was 94%. At 180 days, no implanted stents were found to be fragmented: All of the devices remained at the site of implantation with no stent migration and all stents retained their luminal support. Only moderate inflammation and neoepithelialization were detected by histological assessment at 60, 90, 120, and 180 days. Lumen loss at 180 days was less than 25% of the vessel diameter. Conclusions: The stent with the mechanical and chemical properties described in this study may present the optimal solution of the trade-off between deliverability and luminal stability that is necessary for designing the next generation stent for endovascular therapy of peripheral arterial disease.

Prediction of 2-Year Major Adverse Limb Event-Free Survival After Percutaneous Transluminal Angioplasty and Stenting for Lower Limb Atherosclerosis Obliterans: A Machine Learning-Based Study.

BackgroundThe current scoring systems could not predict prognosis after endovascular therapy for peripheral artery disease. Machine learning could make predictions for future events by learning a specific pattern from existing data. This study aimed to demonstrate machine learning could make an accurate prediction for 2-year major adverse limb event-free survival (MFS) after percutaneous transluminal angioplasty (PTA) and stenting for lower limb atherosclerosis obliterans (ASO).MethodsA lower limb ASO cohort of 392 patients who received PTA and stenting was split to the training set and test set by 4:1 in chronological order. Demographic, medical, and imaging data were used to build machine learning models to predict 2-year MFS. The discrimination and calibration of artificial neural network (ANN) and random forest models were compared with the logistic regression model, using the area under the receiver operating curve (ROCAUC) with DeLong test, and the calibration curve with Hosmer–Lemeshow goodness-of-fit test, respectively.ResultsThe ANN model (ROCAUC = 0.80, 95% CI: 0.68–0.89) but not the random forest model (ROCAUC = 0.78, 95% CI: 0.66–0.87) significantly outperformed the logistic regression model (ROCAUC = 0.73, 95% CI: 0.60–0.83, P = 0.01 and P = 0.24). The ANN model the logistic regression model demonstrated good calibration performance (P = 0.73 and P = 0.28), while the random forest model showed poor calibration (P < 0.01). The calibration curve of the ANN model was visually the closest to the perfectly calibrated line.ConclusionMachine learning models could accurately predict 2-year MFS after PTA and stenting for lower limb ASO, in which the ANN model had better discrimination and calibration. Machine learning-derived prediction tools might be clinically useful to automatically identify candidates for PTA and stenting.

MiR-548j-5p regulates angiogenesis in peripheral artery disease

Peripheral artery disease (PAD) is a vascular disease involving diffuse atherosclerosis, and is associated with increased cardiovascular mortality and morbidity. Critical limb ischemia (CLI) is the most severe complication of PAD. In addition to medical and interventional treatment, therapeutic angiogenesis is a novel therapy for PAD. Circulating microRNAs (miRNAs) are considered key regulators of gene expression, but their role in ischemic-induced angiogenesis is poorly-characterized. There is currently a limited understanding of the specific miRNAs associated with PAD. To determine the regulation of miRNAs, we obtained miRNA profiles using RNA isolated from patients with PAD and a control group. The effects of specific miRNAs on angiogenesis were evaluated by assessing the in vitro angiogenic function of endothelial progenitor cells (EPCs), performing an in vivo angiogenesis assay, and employing a mouse hindlimb ischemic model. Our results demonstrated that circulating miR-548j-5p was significantly reduced in patients with PAD as compared with the controls. miR-548j-5p promoted EPC angiogenesis by enhancing migration and tube formation. The endothelial nitric oxide synthase (NOS) and stromal cell-derived factor (SDF)-1 signaling pathways appeared to be potential targets of miR-548j-5p. Furthermore, the results of a directed in vivo angiogenesis assay of EPCs and a hindlimb ischemia mouse model demonstrated that miR-548j-5p enhanced the capillary density and blood flow recovery in hindlimb ischemia. In conclusion, our data indicated that up-regulation of miR-548j-5p promotes angiogenesis in ischemic tissue and may represent a novel therapeutic approach for PAD.

Engineered clustered myoblast cell injection augments angiogenesis and muscle regeneration in peripheral artery disease

The low survival rate of administered cells due to ischemic and inflammatory environments limits the efficacy of the current regenerative cell therapy in peripheral artery disease (PAD). This study aimed to develop a new method to enhance the efficacy of cell therapy in PAD using cell sheet technology. Clustered cells (CCs) from myoblast cell sheets obtained from C57/BL6 mice were administered into ischemic mouse muscles 7days after induction of ischemia (defined as day 0). Control groups were administered with single myoblast cells (SCs) or saline. Cell survival, blood perfusion of the limb, angiogenesis, muscle regeneration, and inflammation status were evaluated. The survival of administered cells was markedly improved in CCs compared with SCs at days 7 and 28. CCs showed significantly improved blood perfusion, augmented angiogenesis with increased density of CD31+/α-smooth muscle actin+ arterioles, and accelerated muscle regeneration, along with the upregulation of associated genes. Additionally, inflammation status was well regulated by CCs administration. CCs administration increased the number of macrophages and then induced polarization into an anti-inflammatory phenotype (CD11c-/CD206+), along with the increased expression of genes associated with anti-inflammatory cytokines. Our findings suggest clinical potential of rescuing severely damaged limbs in PAD using CCs.

Current Concepts and Future Perspectives of Stem Cell Therapy in Peripheral Arterial Disease

Some advanced stage peripheral arterial disease (PAD) patients will not eligible for revascularization strategies. From the last two decades stem cell therapy (SCT) has been explored as an alternative therapy for no option advanced stage PAD patients. Therapeutic motif of this novel therapy is to promote the collateral vessel formation that will improve the blood flow to ischemic leg that in turn can prevent major amputations. This mini review provides the brief outline of the use of autologous and allogeneic SCT for the treatment of advanced stage PAD

TCT-160 Preprocedural Predictors of Late All-Cause Mortality Following Percutaneous Endovascular Therapy for Peripheral Arterial Disease: A Systematic Review and Meta-Analysis of Hazard Ratios

TCT-160 Preprocedural Predictors of Late All-Cause Mortality Following Percutaneous Endovascular Therapy for Peripheral Arterial Disease: A Systematic Review and Meta-Analysis of Hazard Ratios

Medical Management of Peripheral Artery Disease.

Peripheral artery disease is a highly morbid yet undertreated atherosclerotic disease. The cornerstones of peripheral artery disease therapy consist of smoking cessation, lipid-lowering therapy, and hypertension treatment. More recently, clinical trials have demonstrated that novel antiplatelet and antithrombotic therapies reduce the risk of both cardiovascular and limb events in this patient population. In this review, we highlight the components of optimal medical therapy of peripheral artery disease and the evidence base for these therapies.

Efficacy and Safety of Antiplatelet Therapies in Symptomatic Peripheral Artery Disease: A Systematic Review and Network Meta-Analysis.

BackgroundClopidogrel monotherapy is guideline-recommended in symptomatic peripheral artery disease (PAD). The advent of new antithrombotic strategies prompts an updated analysis of available evidence on antiplatelet therapy for PAD.MethodsWe searched MEDLINE, Embase and CENTRAL through January 2019 for randomised controlled trials and observational studies comparing antiplatelet therapies as monotherapy, dual therapy, or combination with anticoagulants. Efficacy (major adverse cardiovascular events, acute or chronic limb ischaemia, vascular amputation, peripheral revascularisation) and safety (all-cause mortality and overall bleeding) outcomes were evaluated via Bayesian network meta-analyses.ResultsWe analysed 26 randomised controlled trials. Clopidogrel (hazard ratio, HR, 0.78; 95% credible interval [CrI] 0.65-0.93) and ticagrelor (HR 0.80; 95% CrI 0.65-0.98) significantly reduced major adverse cardiovascular events risk compared with aspirin. No significant difference was observed for dual antiplatelet therapy with clopidogrel and aspirin. Vorapaxar significantly reduced limb ischaemia and revascularisation compared with placebo, while dual antiplatelet therapy with clopidogrel and aspirin showed a trend for reduced risk of amputation compared with aspirin (risk ratio 0.68; 95% CrI 0.43-1.04). For all-cause mortality, picotamide, vorapaxar, dipyridamole with aspirin, and ticlopidine showed a significantly lower risk of all-cause mortality vs aspirin. Clopidogrel and ticagrelor showed similar overall bleeding risk vs aspirin, while dual antiplatelet therapy with clopidogrel and aspirin significantly increased bleeding risk.ConclusionThis updated network meta-analysis confirms that clopidogrel significantly decreases the risk of major adverse cardiovascular events compared with aspirin, without increasing bleeding risk. Clopidogrel should remain a mainstay of PAD treatment, at least in patients at higher bleeding risk.