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Circulation Dec 2023Rivaroxaban plus aspirin compared with aspirin alone reduced major cardiac and ischemic limb events after lower extremity revascularization (LER) in the VOYAGER PAD... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Rivaroxaban plus aspirin compared with aspirin alone reduced major cardiac and ischemic limb events after lower extremity revascularization (LER) in the VOYAGER PAD (Vascular Outcomes Study of ASA Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for Peripheral Artery Disease) trial. The effect has not been described in patients undergoing endovascular LER.
METHODS
The VOYAGER PAD trial randomized 6564 patients with symptomatic peripheral artery disease to a double-blinded treatment with 2.5 mg of rivaroxaban BID or matching placebo and 100 mg of aspirin daily. The primary efficacy outcome was a composite of acute limb ischemia, major amputation of a vascular pathogenesis, myocardial infarction, ischemic stroke, or cardiovascular death. The principal safety end point was Thrombolysis in Myocardial Infarction major bleeding. A prespecified subgroup of patients who underwent endovascular revascularization was included.
RESULTS
Endovascular LER occurred in 4379 (66.7%) patients and surgical LER in 2185 (33.3%). Over a 3-year follow-up, rivaroxaban reduced the risk of the primary outcome by 15% (hazard ratio [HR], 0.85 [95% CI, 0.76-0.96]) with an absolute risk reduction of 0.92% at 6 months and 1.04% at 3 years and a consistent benefit in those receiving endovascular (HR, 0.89 [95% CI, 0.76-1.03]) or surgical LER (HR, 0.81 [95% CI, 0.67-0.98]; interaction=0.43). For endovascular-treated patients, rivaroxaban reduced the risk of acute limb ischemia or major amputation of a vascular pathogenesis by 30% (HR, 0.70 [95% CI, 0.54-0.90]; =0.005) with an absolute risk reduction of 1.0% at 6 months and 2.0% at 3 years compared with aspirin alone. Among endovascular-treated patients, the median duration of concomitant dual antiplatelet therapy with clopidogrel treatment was 31 days (interquartile range, 30-58). There was a consistent benefit for rivaroxaban regardless of background clopidogrel. Thrombolysis in Myocardial Infarction major bleeding was significantly higher for the rivaroxaban and aspirin group for the endovascular cohort (HR, 1.66 [95% CI, 1.06-2.59]) with an absolute risk increase of 0.9% at 3 years with no increase in intracranial or fatal bleeding observed (HR, 0.86 [95% CI, 0.40-1.87]; =0.71). Mortality with rivaroxaban was higher in the endovascular-treated patients (HR, 1.24 [95% CI, 1.02-1.52]), although this finding was isolated to specific regions.
CONCLUSIONS
Rivaroxaban added to aspirin or dual antiplatelet therapy after LER for peripheral artery disease reduces ischemic risk and increases major bleeding without an increased risk of intracranial or fatal bleeding. These benefits are consistent in those treated with endovascular and surgical approaches with significant benefits for major adverse limb events. These data support the use of rivaroxaban in addition to aspirin or dual antiplatelet therapy after endovascular intervention for symptomatic peripheral artery disease.
Topics: Humans; Aspirin; Rivaroxaban; Platelet Aggregation Inhibitors; Clopidogrel; Hemorrhage; Peripheral Arterial Disease; Myocardial Infarction; Ischemia; Drug Therapy, Combination
PubMed: 37850397
DOI: 10.1161/CIRCULATIONAHA.122.063806 -
Advances in Surgery Sep 2023Management of acute limb ischemia is complex and time sensitive, and delays in diagnosis and treatment may lead to irreversible tissue damage. Current data challenge the... (Review)
Review
Management of acute limb ischemia is complex and time sensitive, and delays in diagnosis and treatment may lead to irreversible tissue damage. Current data challenge the commonly accepted 6-hour ischemic threshold for acute limb ischemia, although variations in practice remain. Patients with chronic peripheral artery disease may tolerate longer ischemia time due to presence of collateral circulation. Here the authors discuss the presentation, workup, management, and postoperative care of patients with acute limb ischemia, with a focus on how management is altered depending on the duration and degree of ischemia.
Topics: Humans; Limb Salvage; Treatment Outcome; Lower Extremity; Peripheral Arterial Disease; Ischemia; Retrospective Studies; Risk Factors
PubMed: 37536862
DOI: 10.1016/j.yasu.2023.05.003 -
Circulation Research Jul 2023Chronic kidney disease (CKD) accelerates the development of atherosclerosis, decreases muscle function, and increases the risk of amputation or death in patients with...
BACKGROUND
Chronic kidney disease (CKD) accelerates the development of atherosclerosis, decreases muscle function, and increases the risk of amputation or death in patients with peripheral artery disease (PAD). However, the mechanisms underlying this pathobiology are ill-defined. Recent work has indicated that tryptophan-derived uremic solutes, which are ligands for AHR (aryl hydrocarbon receptor), are associated with limb amputation in PAD. Herein, we examined the role of AHR activation in the myopathy of PAD and CKD.
METHODS
AHR-related gene expression was evaluated in skeletal muscle obtained from mice and human PAD patients with and without CKD. AHR (skeletal muscle-specific AHR knockout) mice with and without CKD were subjected to femoral artery ligation, and a battery of assessments were performed to evaluate vascular, muscle, and mitochondrial health. Single-nuclei RNA sequencing was performed to explore intercellular communication. Expression of the constitutively active AHR was used to isolate the role of AHR in mice without CKD.
RESULTS
PAD patients and mice with CKD displayed significantly higher mRNA expression of classical AHR-dependent genes (, , and ) when compared with either muscle from the PAD condition with normal renal function (<0.05 for all 3 genes) or nonischemic controls. AHR significantly improved limb perfusion recovery and arteriogenesis, preserved vasculogenic paracrine signaling from myofibers, increased muscle mass and strength, as well as enhanced mitochondrial function in an experimental model of PAD/CKD. Moreover, viral-mediated skeletal muscle-specific expression of a constitutively active AHR in mice with normal kidney function exacerbated the ischemic myopathy evidenced by smaller muscle masses, reduced contractile function, histopathology, altered vasculogenic signaling, and lower mitochondrial respiratory function.
CONCLUSIONS
These findings establish AHR activation in muscle as a pivotal regulator of the ischemic limb pathology in CKD. Further, the totality of the results provides support for testing of clinical interventions that diminish AHR signaling in these conditions.
Topics: Animals; Humans; Mice; Ischemia; Mice, Knockout; Muscle, Skeletal; Muscular Diseases; Peripheral Arterial Disease; Receptors, Aryl Hydrocarbon; Renal Insufficiency, Chronic
PubMed: 37325935
DOI: 10.1161/CIRCRESAHA.123.322875 -
Primary Care Mar 2024Peripheral artery disease is most often caused by atherosclerosis. Arterial insufficiency from atherosclerotic blockages in the limbs can impair walking distance and put... (Review)
Review
Peripheral artery disease is most often caused by atherosclerosis. Arterial insufficiency from atherosclerotic blockages in the limbs can impair walking distance and put patients with severe disease at risk of limb loss. Management of the disease centers around early diagnosis, supervised exercise therapy and lifestyle modification, optimizing medical care (with the goal of reducing fatal cardiac and cerebrovascular events), and revascularization.
Topics: Humans; Peripheral Arterial Disease; Exercise Therapy; Risk Factors; Ischemia
PubMed: 38278575
DOI: 10.1016/j.pop.2023.07.005 -
Stem Cell Reviews and Reports Nov 2023Circulating endothelial progenitor cells (EPCs) were first described in 1997 by Asahara et al. as "putative endothelial cells" from human peripheral blood. The study of... (Review)
Review
Circulating endothelial progenitor cells (EPCs) were first described in 1997 by Asahara et al. as "putative endothelial cells" from human peripheral blood. The study of endothelial progenitors is also intensifying in several pathologies associated with endothelial damage, including diabetes, myocardial infarction, sepsis, pulmonary arterial hypertension, obstructive bronchopneumopathy and transplantation. EPCs have been studied in several autoimmune diseases with endothelial involvement such as systemic lupus erythematosus, thrombotic thrombocytopenic purpura, antineutrophil cytoplasmic antibodies, vasculitis, rheumatoid arthritis, Goujerot-Sjögren and antiphospholipid syndrome. Factors involved in endothelial damage are due to overexpression of pro-inflammatory cytokines and/or autoantibodies. Management of these pathologies, particularly the long-term use of glucocorticoids and methotrexate, promote atherosclerosis. A lack of standardized assessment of the number and function of EPCs represents a serious challenge for the use of EPCs as prognostic markers of cardiovascular diseases (CVD). The objective of this review was to describe EPCs, their properties and their involvement in several autoimmune diseases.
Topics: Humans; Endothelial Progenitor Cells; Autoimmune Diseases; Arthritis, Rheumatoid; Cytokines; Myocardial Infarction
PubMed: 37676423
DOI: 10.1007/s12015-023-10617-y -
The Surgical Clinics of North America Aug 2023As the number of patients affected by peripheral arterial disease continues to increase, new technical approaches and devices have been developed to provide effective... (Review)
Review
As the number of patients affected by peripheral arterial disease continues to increase, new technical approaches and devices have been developed to provide effective and durable treatment options that will lead to improved outcomes. While the mainstay of endovascular intervention remains mostly balloon-based, several innovative techniques and technologies are in development that may provide new solutions. This review highlights recent endovascular advancements in the management of chronic limb-threatening ischemia and additional adjunctive devices that are needed to improve lesion patency, reduce the need for reintervention, and lead to better patient-centered functional outcomes.
Topics: Humans; Limb Salvage; Treatment Outcome; Endovascular Procedures; Peripheral Arterial Disease; Ischemia; Risk Factors
PubMed: 37455037
DOI: 10.1016/j.suc.2023.05.002 -
Global Heart 2023Previous observational studies have confirmed the relationship between inflammation and acute myocardial infarction (AMI), but genetic evidence is still lacking. The aim...
BACKGROUND
Previous observational studies have confirmed the relationship between inflammation and acute myocardial infarction (AMI), but genetic evidence is still lacking. The aim of this study was to explore the bidirectional association of multiple peripheral inflammatory factors with this disease at the genetic level.
METHODS
Summary data for AMI and several peripheral inflammatory factors (such as interleukin-10 and interleukin-18) were collected from published genome-wide correlation studies. Based on the correlation, independence, and exclusivity assumptions, a total of 9 to 110 instrumental variables were selected from these summary data to predict the above traits. Two-sample Mendelian randomization methods, including inverse-variance weighted (IVW), were used to make causal inferences between exposures and outcomes. Sensitivity analyses including Cochran's Q, MR-Egger intercept, leave-one-out, forest plot, and MR-PRESSO were adopted to assess heterogeneity and horizontal pleiotropy.
RESULTS
The IVW reported that elevated peripheral levels of interleukin-10 and interleukin-18 were nominally associated with a reduced risk of AMI (OR = 0.876, 95% CI = 0.788 ~ 0.974, P = 0.015; OR = 0.934, 95% CI = 0.875 ~ 0.997, P = 0.040). The IVW also reported that the risk of AMI nominally increased the peripheral level of interleukin-10 (OR = 1.062, 95% CI = 1.003 ~ 1.124, P = 0.040). No significant heterogeneity or horizontal pleiotropy were found by sensitivity analyses.
CONCLUSION
Both interleukin-10 and interleukin-18 were peripheral inflammatory factors genetically associated with AMI. In particular, combined with previous knowledge, interleukin-10 may have a protective effect on the onset, progression, and prognosis of the disease.
Topics: Humans; Interleukin-10; Interleukin-18; Mendelian Randomization Analysis; Inflammation; Myocardial Infarction
PubMed: 37811136
DOI: 10.5334/gh.1269 -
International Journal of Molecular... Oct 2023Atherosclerosis constitutes a persistent inflammatory ailment, serving as the predominant underlying condition for coronary artery disease (CAD), peripheral artery... (Review)
Review
Atherosclerosis constitutes a persistent inflammatory ailment, serving as the predominant underlying condition for coronary artery disease (CAD), peripheral artery disease (PAD), and cerebrovascular disease. The progressive buildup of plaques within the walls of medium- and large-caliber arteries characterizes the atherosclerotic process. This accumulation results in significant narrowing that impedes blood flow, leading to critical tissue oxygen deficiency. Spontaneous blockage of thrombotic vessels can precipitate stroke and myocardial infarction, which are complications representing the primary global causes of mortality. Present-day models for predicting cardiovascular risk incorporate conventional risk factors to gauge the likelihood of cardiovascular events over a ten-year span. In recent times, researchers have identified serum biomarkers associated with an elevated risk of atherosclerotic events. Many of these biomarkers, whether used individually or in combination, have been integrated into risk prediction models to assess whether their inclusion enhances predictive accuracy. In this review, we have conducted a comprehensive analysis of the most recently published literature concerning serum biomarkers associated with atherosclerosis. We have explored the potential utility of incorporating these markers in guiding clinical decisions.
Topics: Humans; Atherosclerosis; Coronary Artery Disease; Myocardial Infarction; Plaque, Atherosclerotic; Biomarkers; Risk Factors
PubMed: 37958528
DOI: 10.3390/ijms242115546 -
Archives of Cardiovascular Diseases Jan 2024Cancer is associated with a hypercoagulable state and is a well-known independent risk factor for venous thromboembolism, whereas the association between cancer and... (Review)
Review
Cancer is associated with a hypercoagulable state and is a well-known independent risk factor for venous thromboembolism, whereas the association between cancer and arterial thromboembolism is less well established. Arterial thromboembolism, primarily defined as myocardial infarction or stroke is significantly more frequent in patients with cancer, independently of vascular risk factors and associated with a three-fold increase in the risk of mortality. Patients with brain cancer, lung cancer, colorectal cancer and pancreatic cancer have the highest relative risk of developing arterial thromboembolism. Antithrombotic treatments should be used with caution due to the increased risk of haemorrhage, as specified in current practice guidelines.
Topics: Humans; Stroke; Hemorrhage; Risk Factors; Myocardial Infarction; Venous Thromboembolism; Atrial Fibrillation; Neoplasms
PubMed: 38057257
DOI: 10.1016/j.acvd.2023.11.007 -
Blood Advances Nov 2023In ischemic tissue, platelets can modulate angiogenesis. The specific factors influencing this function, however, are poorly understood. Here, we characterized the...
In ischemic tissue, platelets can modulate angiogenesis. The specific factors influencing this function, however, are poorly understood. Here, we characterized the complement anaphylatoxin C5a-mediated activation of C5a receptor 1 (C5aR1) expressed on platelets as a potent regulator of ischemia-driven revascularization. We assessed the relevance of the anaphylatoxin receptor C5aR1 on platelets in patients with coronary artery disease as well as those with peripheral artery disease and used genetic mouse models to characterize its significance for ischemia and growth factor-driven revascularization. The presence of C5aR1-expressing platelets was increased in the hindlimb ischemia model. Ischemia-driven angiogenesis was significantly improved in C5aR1-/- mice but not in C5-/- mice, suggesting a specific role of C5aR1. Experiments using the supernatant of C5a-stimulated platelets suggested a paracrine mechanism of angiogenesis inhibition by platelets by means of antiangiogenic CXC chemokine ligand 4 (CXCL4, PF4). Lineage-specific C5aR1 deletion verified that the secretion of CXCL4 depends on C5aR1 ligation on platelets. Using C5aR1-/-CXCL4-/- mice, we observed no additional effect in the revascularization response, underscoring a strong dependence of CXCL4 secretion on the C5a-C5aR1-axis. We identified a novel mechanism for inhibition of neovascularization via platelet C5aR1, which was mediated by the release of antiangiogenic CXCL4.
Topics: Humans; Mice; Animals; Intercellular Signaling Peptides and Proteins; Anaphylatoxins; Ischemia; Receptor, Anaphylatoxin C5a
PubMed: 37257194
DOI: 10.1182/bloodadvances.2021006891