IVUS Improves Outcomes With SUPERA Stents for the Treatment of Superficial Femoral-Popliteal Artery Disease.

BACKGROUND: Nitinol interwoven bare metal stents represent an advancement in stent technology; however, nominal deployment remains an area of focus. Intravascular ultrasound (IVUS) has been shown to improve outcomes in both the coronary and peripheral vasculature by providing the operator with greater vessel detail; however, the use of adjunctive IVUS with nitinol bare metal stents has not been widely studied. This studies aims to determine the effect of IVUS when used adjunctively with nitinol interwoven bare metal stents in the management of femoropopliteal lesions. DESIGN: Retrospective study. METHODS: This study included a cohort of 200 consecutive patients with peripheral artery disease. All patients were treated with ≥1 Supera bare metal stent, and 91 received adjunctive IVUS imaging prior to stent deployment. Deployment conditions of nominal, compressed, and elongated were measured, and the primary clinical outcomes included target lesion reintervention, amputation, and mortality. This study also showed that 8.3 number needed to treat (NNT) patients must be treated with IVUS to avoid an additional revascularization event. RESULTS: The patients who received IVUS had a significantly greater number of nominally deployed stents (p<0.001). Patients who had IVUS imaging also had significantly lower reintervention rates compared with those who did not receive IVUS imaging (p=0.047). CONCLUSION: The IVUS and angiography decreases clinically-driven target lesion reintervention and increases nominal deployment compared with angiography alone in femoropopliteal lesions treated with interwoven bare metal nitinol stents. CLINICAL IMPACT: Endovascular surgones may conisder the adjuctive use of IVUS when using the Supera stent for the treatment of infra inguinal superficial femoral artery lesions. The adjunct use of IVUS may lead to improved sizing, vessel prep, deployment, and ultiamtely reduction in CD-TLR.

Comparison and Analysis between the NAV6 Embolic Protection Filter and SpiderFX EPD Filter in Superficial Femoral Artery Lesions.

OBJECTIVE: To compare the safety and efficacy between the SpiderFX EPD and Emboshield NAV6 filter in the collection of embolic debris created from lower limb atherectomy procedures in patients with PAD. MATERIALS AND METHODS: Between January 2014 and October 2015, 507 patients with symptomatic peripheral artery disease were treated with directional atherectomy (SilverHawk), rotational atherectomy (JetStream), or laser atherectomy (Turbo Elite) based on operator discretion. Emboshield NAV6 (n = 161) and SpiderFX (n = 346) embolic protection devices were used with each of the 3 atherectomy devices. The primary study endpoint was 30-day freedom from major adverse events (MAEs). An MAE was defined as death, MI, TVR, thrombosis, dissection, distal embolization, perforation at the level of the filter, and unplanned amputation. A descriptive comparison of the MAE rates between Emboshield NAV6 and SpiderFX embolic protection devices was conducted. RESULTS: The freedom from major adverse event (MAE) rate was 92.0% (CI: 86.7%, 95.7%) in patients who received an Emboshield NAV6 filter compared to 91.6% (CI: 88.2%, 94.3%) in patients who received the SpiderFX filter (p=0.434). The lower limit of 86.7% freedom from major adverse event rate in the Emboshield NAV6 group was above the performance goal of 83% (p < 0.0008). CONCLUSIONS: There were no significant clinical outcome differences between Emboshield NAV6 and SpiderFX EPD filters in the treatment of lower extremities. This evaluation indicates the safety and efficacy to use either filter device to treat PAD patients with lower extremity lesions.

Does Caffeine Consumption Increase the Risk of New-Onset Atrial Fibrillation?

OBJECTIVE: Caffeine has been considered a trigger for atrial fibrillation (AF). We conducted a meta-analysis including a dose-response analysis to assess the relationship between caffeine consumed and incidence of AF. METHODS: Data from selected studies represented 176,675 subjects (AF in 9,987 [5.7%]). Caffeine content varied widely, ranging from 40 to 180 mg per cup of coffee. For purposes of the calculations in this study, we assumed 140 mg of caffeine in a standard 12-oz cup of coffee. RESULTS: No significant difference was found in AF incidence when the subjects consuming less than 2 cups of coffee per day were compared to subjects with higher consumption, 1.068 (0.937-1.216). The risk of AF was higher among subjects consuming less than 2 cups of coffee daily when compared to higher daily consumption subjects. A lower incidence of AF was found among people consuming more than 436 mg daily. CONCLUSION: The incidence of AF is not increased by coffee consumption. In fact, we found a lower incidence of AF when caffeine consumption exceeded 436 mg/day. Therefore, based on available evidence there is no association between caffeine intake and AF risk.

Effects of Ischemic Reperfusion Injury and Remote Conditioning on Passive Leg Raising-Induced Brachial-Artery Dilation.

OBJECTIVES: Passive leg raising (PLR) has been proposed to assess arterial vasodilator reserve and possibly endothelial function. Since endothelial function is sensitive to ischemic-reperfusion (I-R) injury, we determined the effects of I-R injury and ischemic conditioning on PLR-induced brachial-artery dilation (BAD), i.e. PLR-BAD. METHODS: We induced PLR-BAD before and after ipsilateral arm I-R injury (7.5 min of occlusion) in 20 healthy males aged 29 ± 6 years. The protocol was repeated in combination with remote conditioning stimuli (3 × 30 s of contralateral arm occlusions). RESULTS: PLR resulted in significant BAD (3.85%, p < 0.001) before but not after prolonged ischemia (0.25%, p = 0.38). I-R injury, along with either preischemic or postischemic conditioning restored the PLR-BAD response (before: 3.11%, p < 0.001 and after: 3.74%, p < 0.001). CONCLUSIONS: I-R injury blunts the BAD induced by PLR. Remote pre- and postconditioning restore this response. These findings are similar to those previously reported using hyperemia and ultrasound to assess BAD.

The ankle-brachial index is related to left ventricular ejection fraction in bonnet macaques.

UNLABELLED: Low ankle-brachial index (ABI) is a marker of peripheral arterial disease associated with higher cardiovascular risk. ABI has been found to be influenced by left ventricular ejection fraction (LVEF), but this relation is confounded by atherosclerosis. OBJECTIVES: Since nonhuman primates have a low incidence of atherosclerosis, we sought to evaluate the effect of LVEF on ABI in 24 healthy female bonnet macaques (age 83 ± 21 months). METHODS: LVEF was determined by echocardiography during anesthesia with ketamine. ABI was determined using automatic blood pressure cuff. RESULTS: Mean LVEF was 73 ± 6%. Mean ABI was 1.03 (range 0.78-1.17) with similar right and left lower limb values (p = 0.78). On univariate analysis, mean ABI was significantly correlated with LVEF (r = 0.58, p = 0.003) but not with age, crown-rump length or weight. Mean LVEF increased in a stepwise manner from lowest to highest ABI tertile (68 ± 6 vs. 73 ± 4 vs. 77 ± 5%, p = 0.008). On ordinal regression and forced multivariate linear analyses, ABI status was independently related to LVEF. CONCLUSIONS: ABI is influenced by left ventricular systolic function but not age, height, weight or mass index in bonnet macaques. Left ventricular systolic function should be accounted for when considering ABI measurements.

Cardiac lineage protein-1 (CLP-1) regulates cardiac remodeling via transcriptional modulation of diverse hypertrophic and fibrotic responses and angiotensin II-transforming growth factor ß (TGF-ß1) signaling axis.

It is well known that the renin-angiotensin system contributes to left ventricular hypertrophy and fibrosis, a major determinant of myocardial stiffness. TGF-ß1 and renin-angiotensin system signaling alters the fibroblast phenotype by promoting its differentiation into morphologically distinct pathological myofibroblasts, which potentiates collagen synthesis and fibrosis and causes enhanced extracellular matrix deposition. However, the atrial natriuretic peptide, which is induced during left ventricular hypertrophy, plays an anti-fibrogenic and anti-hypertrophic role by blocking, among others, the TGF-ß-induced nuclear localization of Smads. It is not clear how the hypertrophic and fibrotic responses are transcriptionally regulated. CLP-1, the mouse homolog of human hexamethylene bis-acetamide inducible-1 (HEXIM-1), regulates the pTEFb activity via direct association with pTEFb causing inhibition of the Cdk9-mediated serine 2 phosphorylation in the carboxyl-terminal domain of RNA polymerase II. It was recently reported that the serine kinase activity of Cdk9 not only targets RNA polymerase II but also the conserved serine residues of the polylinker region in Smad3, suggesting that CLP-1-mediated changes in pTEFb activity may trigger Cdk9-dependent Smad3 signaling that can modulate collagen expression and fibrosis. In this study, we evaluated the role of CLP-1 in vivo in induction of left ventricular hypertrophy in angiotensinogen-overexpressing transgenic mice harboring CLP-1 heterozygosity. We observed that introduction of CLP-1 haplodeficiency in the transgenic α-myosin heavy chain-angiotensinogen mice causes prominent changes in hypertrophic and fibrotic responses accompanied by augmentation of Smad3/Stat3 signaling. Together, our findings underscore the critical role of CLP-1 in remodeling of the genetic response during hypertrophy and fibrosis.

Left ventricular systolic function in sickle cell anemia: a meta-analysis.

BACKGROUND: We sought to evaluate whether patients with sickle cell anemia (SCA) have left ventricular (LV) systolic dysfunction. METHODS AND RESULTS: We conducted a Medline, Embase, Ebscohost, and Google scholar literature search articles published before April 2010. All studies that compared any measure of LV function (eg, ejection fraction [EF], fractional shortening [FS], or cardiac index [CI]) between normal control subjects and SCA (hemoglobin SS) patients were included. Among 57 studies that qualified for review, 19 studies including 841 SCA patients and 554 control subjects met the inclusion criteria. There were no significant differences in either LVEF (Hedge g = 0.15; 95% confidence interval -0.84 to 1.14; P = .76) or FS (P = .28) between SCA patients and control subjects. CI was significantly higher (P < .001) and LV end-systolic stress-volume index (load independent) was significantly lower (P < .001) in SCA patients. All LV systolic measures inversely correlated with age (all P < .001). LV end-systolic and -diastolic dimensions were significantly higher in SCA patients and increased with age. CONCLUSIONS: SCA patients have similar load-dependent but lower load-independent measures of LV systolic function than control subjects. SCA is associated with LV dilation. LV structural and functional abnormalities appear to be age dependent with progressive LV dilation and impairment over time.

Comparison of passive leg raising and hyperemia on macrovascular and microvascular responses.

Passive leg raising is a simple diagnostic maneuver that has been proposed as a measure of arterial vasodilator reserve and possibly endothelial function. While passive leg raising has previously been shown to lower blood pressure, increase flow velocity and cause brachial artery dilation, its effects on microvascular flow has not been well studied. Also, passive leg raising has been directly compared previously to upper arm but never to lower arm occlusion of blood flow induced hyperemia responses. We compared changes in macrovascular indices measured by brachial artery ultrasound and microvascular perfusion measured by Laser Doppler Flowmetry induced by passive leg raising to those provoked by upper arm and lower arm induced hyperemia in healthy subjects. Upper arm induced hyperemia increased mean flow velocity by 398%, induced brachial artery dilatation by 16.3%, and increased microvascular perfusion by 246% (p<.05 for all). Lower arm induced hyperemia increased flow velocity by 227%, induced brachial artery dilatation by 10.8%, and increased microvascular perfusion by 281%. Passive leg raising increased flow velocity by 29% and brachial artery dilatation by 5.6% (p<.05 for all), but did not change microvascular perfusion (-5%, p=ns). In conclusion, passive leg raising increases flow velocity orders of magnitude less than does upper arm or lower arm induced hyperemia. Passive leg raising-induced brachial artery dilatation is less robust than either of these hyperemic techniques. Finally, although upper arm and lower arm hyperemia elicits macrovascular and microvascular responses, passive leg raising elicits only macrovascular responses.

Determination of heart rate variability with an electronic stethoscope.

INTRODUCTION: Heart rate variability (HRV) is widely used to characterize cardiac autonomic function by measuring beat-to-beat alterations in heart rate. Decreased HRV has been found predictive of worse cardiovascular (CV) outcomes. HRV is determined from time intervals between QRS complexes recorded by electrocardiography (ECG) for several minutes to 24 h. Although cardiac auscultation with a stethoscope is performed routinely on patients, the human ear cannot detect heart sound time intervals. The electronic stethoscope digitally processes heart sounds, from which cardiac time intervals can be obtained. METHODS: Accordingly, the objective of this study was to determine the feasibility of obtaining HRV from electronically recorded heart sounds. We prospectively studied 50 subjects with and without CV risk factors/disease and simultaneously recorded single lead ECG and heart sounds for 2 min. RESULTS: Time and frequency measures of HRV were calculated from R-R and S1-S1 intervals and were compared using intra-class correlation coefficients (ICC). CONCLUSION: The majority of the indices were strongly correlated (ICC 0.73-1.0), while the remaining indices were moderately correlated (ICC 0.56-0.63). In conclusion, we found HRV measures determined from S1-S1 are in agreement with those determined by single lead ECG, and we demonstrate and discuss differences in the measures in detail. In addition to characterizing cardiac murmurs and time intervals, the electronic stethoscope holds promise as a convenient low-cost tool to determine HRV in the hospital and outpatient settings as a practical extension of the physical examination.

Revascularization Strategies for Patients With Femoropopliteal Peripheral Artery Disease.

BACKGROUND: No adequately powered studies exist to compare major clinical outcomes after endovascular therapy (EVT) with stent implantation vs bypass surgery (BSx) for symptomatic femoropopliteal peripheral artery disease. OBJECTIVES: This study sought to perform a pooled analysis of individual patient data from all randomized controlled trials comparing EVT vs BSx. METHODS: Principal investigators of 5 of 6 available randomized controlled trials agreed to pool individual patient data. The primary endpoint was major adverse limb events, a composite of all-cause death, major amputation, or target limb reintervention. Secondary endpoints included amputation-free survival, individual major adverse limb event components, and primary patency. Early complications were bleeding, infection, or all-cause death within 30 days. RESULTS: A total of 639 patients were analyzed with a mean age of 68.1 ± 9.1 years and 29.0% women. Baseline characteristics were comparable between groups. At 2 years, there were no significant differences between patients who received EVT and those who received BSx regarding major adverse limb events (40.1% vs 36.4%; log-rank P = 0.447; adjusted HR [aHR]: 1.04; 95% CI: 0.80-1.36), amputation-free survival (88.1% vs 90.0%; log-rank P = 0.455; aHR for death or amputation: 1.04; 95% CI: 0.63-1.71) and the other secondary endpoints except for primary patency, which was lower in patients who received EVT vs those who received BSx (51.2% vs 61.3%; log-rank P = 0.024; aHR for loss of primary patency: 1.31; 95% CI: 1.02-1.69). EVT was associated with significantly lower rates of early complications (6.8% vs 22.6%; P < 0.001) and shorter hospital stay (3.1 ± 4.2 days vs 7.4 ± 4.9 days; P < 0.001). CONCLUSIONS: These findings further support the efficacy and safety of EVT as an alternative to BSx in patients with symptomatic femoropopliteal peripheral artery disease.

Prion protein as a mediator of neurocardiosympathetic interactions.

A proteomic approach to study cardiovascular disease includes the examination of proteins associated with risk factors such as left ventricular hypertrophy (LVH). PrP(C) is a host-coded membrane-bound glycoprotein found in most cell types, including myocardium, and whose physiological function is uncertain. We have taken a selective proteomic approach and performed mechanistic studies to determine whether PrP(C) levels are related to left ventricular (LV) structure or function. Echocardiograms were performed at baseline in 65 mice comprising three strains of the same C57Bl/6J × 129SV genetic background but expressing different levels of PrP(C) (wild-type mice (WT), PrP(-/-) , and PrP(C) over-expressing transgenic mice (tga20)). There were no significant differences in LV mass or LV ejection fraction between the three groups. Either normal saline (n = 60) or isoproterenol (n = 55) was then administered intraperitoneally (50 mg/kg/day) for 5 days/wk for two consecutive weeks to induce LVH. Body weight decreased significantly in the PrP(-/-) group (18%). On multivariate analysis, higher LV mass index posttreatment was independently associated with the tga20 group (versus PrP(-/-) versus WT, p = 0.002) after adjusting for treatment (isoproterenol versus saline), and weight change (r(2) = 0.13 for model, p = 0.016). Therefore, PrP(C) appears unrelated to LV mass and function in the basal state. Isoproterenol causes transient enhancement of PrP(C) expression in WT mice and a more pronounced increase in tga20 mice at 2 h posttreatment. Overexpression of PrP(C) in the tga20 group may be associated with higher LV mass after a 2 wk regimen of isoproterenol.

Evaluation of arterial structure and function in pediatric patients with end-stage renal disease on dialysis and after renal transplantation.

CVD is a major cause of morbidity and mortality in pediatric patients with CKD. It is unclear whether vascular abnormalities in these patients are reversible, and if transplantation portends salutary effects on arterial function. We compared FMD, PWV, AI75, and CIMT in 15 dialysis (D), 14 transplant patients (T), and 15 controls (C), and their associations with cardiovascular risk factors. There was stepwise lower FMD (p < 0.001), higher AI75 (p < 0.001), higher PWV (p = 0.01), and higher CIMT SDS for age (p = 0.03) and height (p = 0.006) in the D group than T and C groups. FMD, PWV, and CIMT were unrelated to dialysis duration or time from transplantation. On multivariate analysis, group status was independently associated with FMD (ß = 3.15, p = 0.002), AI75 (ß = -5.95, p = 0.01), PWV (ß = -0.57, p = 0.07) and CIMT (ß = -0.02, p = 0.04) and CIMT SDS for height (ß = -0.541, p = 0.009). FMD is lower and AI75, PWV and CIMT are higher in pediatric patients maintained on D than T/C. T patients have similar AI75, PWV and CIMT to C although FMD remains reduced. These findings suggest that transplantation stabilizes or improves CKD associated arteriopathy.

Drug coated balloon improves outcomes of sub-optimal Supera deployment in the intermediate term.

Sub-Optimal deployment of Self expanding interwoven stents (Supera) has been shown to increase the rate of Clinically Driven Target Lesion Revascularization (CD-TLR). Meanwhile, drug coated balloons (DCB) have been shown to reduce CD-TLR in the femoral-popliteal segment in de- novo and restenotic lesions. However, the clinical effects of vessel preparation with DCB in nominal, compressed, and elongated Supera has not been widely studied. The purpose of this study is to assess the outcomes of clinically driven re-intervention, major amputations, and mortality in relation to the use of DCB as vessel preparation in different deployment conditions (nominal, compressed, elongated) of the Supera stent. Patient chart data was collected at a single center hospital between March 2015 and May 2020. All patients were adults (≥ 18 years old) and were treated with at least one (≥ 1) Supera stent. Deployment status was extrapolated from anonymized angiograms. The primary endpoint of this study was CD-TLR. Secondary endpoints included amputation and mortality rates associated with each deployment condition. A total of 670 limbs were treated and patients were followed for 36 months. Nominal stent deployment was observed in 337 limbs, followed by elongated condition (n = 176), then by compressed conditions (n = 159). CD-TLR was observed most frequently with elongated deployment. Drug coated balloons were used as vessel prep prior to stenting and showed a protective effect regardless of deployment status; O.R = 0.44 (CI 0.30-0.66, p < .05).

Analysis of Interwoven Nitinol Stenting for the Treatment of Critical Limb Ischemia: Outcomes From an Average 3-Year Follow-up Period.

We assessed the clinical outcomes of patients with critical limb-threatening ischemia (CLTI) who underwent interwoven nitinol stent (Supera) implantation for significant stenoses of the femoropopliteal segment. In this retrospective cohort study, 116 consecutive patients with CLTI who were treated with Supera stents between September 2015 and March 2020 were included in this analysis. Primary endpoint analysis was completed for amputation-free survival, target lesion revascularization (TLR), and mortality. After a mean follow-up time of 3.4 years, 21 (18%) patients had undergone amputations, 3 (2.6%) died, and, overall, the amputation-free survival rate was 81%. TLR occurred in 21 (18%) patients, resulting in the freedom from target lesion revascularization of 82%. The average Wagner score for all patients was 2.8 ± 1.1. A subgroup analysis of 57 patients revealed a median ulcer size of 3.0 cm2 [1.65, 9.0], with complete healing for 45 patients by 20 months. The Wagner score of this subgroup decreased by an average of 3.4 ± .9 points. Supera stents can be used together with other endovascular therapies and are a safe and effective treatment modality for CLTI.

Determinants of Drug-Coated Balloon Failure in Patients Undergoing Femoropopliteal Arterial Intervention.

BACKGROUND: Drug-coated balloons (DCB) are frequently used to treat femoropopliteal artery disease. However, patency loss occurs in ≥10% of patients within 12 months posttreatment with poor understanding of the underlying mechanisms. OBJECTIVES: The authors sought to investigate the determinants of DCB failure in femoropopliteal disease. METHODS: Data from randomized clinical trials (IN.PACT SFA, MDT-2113 SFA Japan) and 2 prespecified imaging cohorts of the IN.PACT Global Clinical Study were included. Influential procedural characteristics were evaluated by an independent angiographic core laboratory. The primary endpoint was DCB failure (patency loss during follow-up). Additional endpoints were binary restenosis and clinically driven target lesion revascularization. Multivariable analyses evaluated the clinical, anatomical, and procedural predictors of DCB failure. RESULTS: Included were 557 participants with single lesions and 12-month core laboratory-adjudicated duplex ultrasonography. Key clinical characteristics were as follows: mean age 68.8 years, 67.5% male, 87.6% with hypertension, 76.9% with hyperlipidemia, 40.5% with diabetes mellitus, 90.5% in Rutherford Classification Category (RCC) 2 to 3, and 9.5% in RCC 4 to 5. Average length and reference vessel diameter (RVD) were 16.37 cm and 4.66 mm, respectively; 49.7% of lesions were totally occluded. In multivariable analysis, only residual stenosis >30% was associated with patency loss, whereas residual stenosis >30% and smaller preprocedure RVD were associated with increased binary restenosis risk. RCC >3 and residual stenosis >30% were associated with increased 12-month clinically driven target lesion revascularization risk. CONCLUSIONS: Patency loss after DCB treatment was influenced by procedural and clinical factors. Residual stenosis >30%, smaller preprocedure RVD, and higher RCC may be considered predictors of increased risk of DCB failure and its components in femoropopliteal artery disease. (Randomized Trial of IN.PACT Admiral® Drug Coated Balloon vs Standard PTA for the Treatment of SFA and Proximal Popliteal Arterial Disease [INPACT SFA I]; NCT01175850; IN.PACT Admiral Drug-Coated Balloon vs. Standard Balloon Angioplasty for the Treatment of Superficial Femoral Artery [SFA] and Proximal Popliteal Artery [PPA] [INPACT SFA II]; NCT01566461; MDT-2113 Drug-Eluting Balloon vs. Standard PTA for the Treatment of Atherosclerotic Lesions in the Superficial Femoral Artery and/or Proximal Popliteal Artery [MDT-2113 SFA]; NCT01947478; IN.PACT Global Clinical Study; NCT01609296).

Reduced water induced skin wrinkling in congestive heart failure.

Water immersion skin wrinkling (WISW) of the fingertips may reflect central autonomic function. We found lower WISW in 60 heart failure patients versus controls (1.6±0.67 vs. 2.5±1.1, p<0.001), linking a cardiovascular disorder to reduced WISW.

Aneurysmal Dilatation of the Superficial Femoral Artery After Endovascular Intervention.

A patient with occlusion of the left superficial femoral artery (SFA) underwent endovascular intervention. Six-month follow-up angiography revealed aneurysmal dilatation of the previously stented artery. This finding may be a result of maladaptive vascular remodeling or arterial injury resulting in aneurysmal dilatation secondary to subintimal crossing, atherectomy, and paclitaxel therapies. (Level of Difficulty: Beginner.).

Considerations for Patients With Peripheral Artery Disease During the COVID-19 Pandemic.

New York City was one of the epicenters of the COVID-19 pandemic. The management of peripheral artery disease (PAD) during this time has been a major challenge for health care systems and medical personnel. This document is based on the experiences of experts from various medical fields involved in the treatment of patients with PAD practicing in hospitals across New York City during the outbreak. The recommendations are based on certain aspects including the COVID-19 infection status as well as the clinical PAD presentation of the patient. Our case-based algorithm aims at guiding the treatment of patients with PAD during the pandemic in a safe and efficient way.

Meta-Analysis of Anticoagulation Therapy for the Prevention of Cardiovascular Events in Patients With Peripheral Arterial Disease.

Peripheral artery disease (PAD) remains a major cause of morbidity and future cardiovascular events despite advancement in the surgical interventions and optimal medical therapy. The aim of our study is to evaluate the efficacy and safety of anticoagulation (AC) therapy for reducing cardiovascular and limb events in patients with PAD. PUBMED, Medline, and Cochrane Library were searched through 2020 for randomized clinical trials comparing major adverse cardiovascular events (MACE) and risk of major bleeding (MB), between AC and standard of care (SOC) therapy, among patients with PAD. Meta-analysis was performed using weighted pooled absolute risk difference (RD) with 95% confidence interval (CI) and fixed effects model for overall and sub-groups of full dose (FD) and low dose (LD) AC therapies. Amongst 17,684 patients from 7 different studies, the addition of AC to SOC therapy was associated with MACE reduction (RD -0.022, 95% CI -0.033 to -0.012, p <0.001) and increased MB (RD 0.02, 95% CI 0.014 to 0.025, p <0.001). For FD, MACE reduction was (RD -0.021, 95% CI -0.042 to 0.001, p = 0.061) and MB (RD 0.036, 95% CI 0.025 to 0.047, p <0.001). For LD, MACE reduction was (RD -0.023, 95% CI -0.035 to -0.011, p <0.001) and MB (RD 0.011, 95% CI 0.005 to 0.017, p <0.001). In conclusion, addition of AC to the current SOC therapy can mitigate future MACE events in patients with PAD albeit at risk of increased bleeding. LD AC is associated with an efficacy/safety net benefit compared to FD AC therapy.