A meta-analysis and systematic review of venous thromboembolism prophylaxis in patients undergoing vascular surgery procedures.

OBJECTIVE: Perioperative venous thromboembolism (VTE) is generally considered preventable. Whereas the non-vascular surgery literature is rich in providing data about the impact of VTE prophylaxis on VTE outcomes, vascular surgery data are relatively sparse on this topic. This study sought to evaluate the evidence for VTE prophylaxis specifically for the population of vascular surgery patients. METHODS: A systematic search was conducted in MEDLINE, Cochrane, and Embase databases in December 2018. Included were studies reporting primary and secondary outcomes for common vascular surgery procedures (open aortic operation, endovascular aneurysm repair [EVAR], peripheral artery bypass, amputation, venous reflux operation). A meta-analysis was performed comparing the patients who did not receive VTE prophylaxis and had VTE complications with patients who developed VTE despite receiving prophylaxis. RESULTS: From 3757 uniquely identified articles, 42 publications met the criteria for inclusion in this review (1 for the category of all vascular operations, 5 for open aortic reconstructions, 2 for EVAR, 1 for open aortic surgery or EVAR, 3 for abdominal or bypass surgery, 2 for peripheral bypass surgery, 2 for amputations, 1 for vascular trauma, and 25 for surgical treatment of superficial venous disease). Five studies met the criteria for inclusion in the meta-analysis. The results demonstrated slightly lower relative risk for development of VTE among patients receiving VTE prophylaxis (relative risk, 0.70; 95% confidence interval, 0.26-1.87). After open aortic reconstruction, the risk of VTE is 13% to 18% and is not reduced by VTE prophylaxis. For EVAR patients, the risk of VTE without prophylaxis is 6%. For patients undergoing peripheral bypass surgery and not receiving therapeutic or prophylactic anticoagulation, the risk of VTE is <2%. For patients undergoing amputations, VTE prophylaxis reduces the risk of VTE. For patients undergoing surgical treatment of superficial venous disease, there is an abundance of literature exploring the utility of VTE prophylaxis, but the evidence is conflicting; some studies demonstrated a benefit, whereas others showed no reduction of VTE with prophylaxis. CONCLUSIONS: Overall, there is a paucity of literature that addresses the effectiveness of VTE prophylaxis specifically in the population of vascular surgery patients. Our meta-analysis of the literature does not demonstrate a statistically significant benefit of VTE prophylaxis among the vascular surgery patients evaluated; however, it does suggest a low incidence of VTE among patients who receive VTE prophylaxis. Clinicians should identify the patients at high risk for development of postoperative VTE as the risk-benefit ratio may favor VTE prophylaxis in a selected group of patients. Clinicians should use their judgment and established VTE risk prediction models to assess VTE risk for patients. Vascular surgeons should consider reporting VTE incidence as a secondary outcome in publications.

Apelin protects against abdominal aortic aneurysm and the therapeutic role of neutral endopeptidase resistant apelin analogs.

Abdominal aortic aneurysm (AAA) remains the second most frequent vascular disease with high mortality but has no approved medical therapy. We investigated the direct role of apelin (APLN) in AAA and identified a unique approach to enhance APLN action as a therapeutic intervention for this disease. Loss of APLN potentiated angiotensin II (Ang II)-induced AAA formation, aortic rupture, and reduced survival. Formation of AAA was driven by increased smooth muscle cell (SMC) apoptosis and oxidative stress in Apln-/y aorta and in APLN-deficient cultured murine and human aortic SMCs. Ang II-induced myogenic response and hypertension were greater in Apln-/y mice, however, an equivalent hypertension induced by phenylephrine, an α-adrenergic agonist, did not cause AAA or rupture in Apln-/y mice. We further identified Ang converting enzyme 2 (ACE2), the major negative regulator of the renin-Ang system (RAS), as an important target of APLN action in the vasculature. Using a combination of genetic, pharmacological, and modeling approaches, we identified neutral endopeptidase (NEP) that is up-regulated in human AAA tissue as a major enzyme that metabolizes and inactivates APLN-17 peptide. We designed and synthesized a potent APLN-17 analog, APLN-NMeLeu9-A2, that is resistant to NEP cleavage. This stable APLN analog ameliorated Ang II-mediated adverse aortic remodeling and AAA formation in an established model of AAA, high-fat diet (HFD) in Ldlr-/- mice. Our findings define a critical role of APLN in AAA formation through induction of ACE2 and protection of vascular SMCs, whereas stable APLN analogs provide an effective therapy for vascular diseases.

Hypoxia and Ischemia Promote a Maladaptive Platelet Phenotype.

OBJECTIVE: Reduced blood flow and tissue oxygen tension conditions result from thrombotic and vascular diseases such as myocardial infarction, stroke, and peripheral vascular disease. It is largely assumed that while platelet activation is increased by an acute vascular event, chronic vascular inflammation, and ischemia, the platelet activation pathways and responses are not themselves changed by the disease process. We, therefore, sought to determine whether the platelet phenotype is altered by hypoxic and ischemic conditions. APPROACH AND RESULTS: In a cohort of patients with metabolic and peripheral artery disease, platelet activity was enhanced, and inhibition with oral antiplatelet agents was impaired compared with platelets from control subjects, suggesting a difference in platelet phenotype caused by the disease. Isolated murine and human platelets exposed to reduced oxygen (hypoxia chamber, 5% O2) had increased expression of some proteins that augment platelet activation compared with platelets in normoxic conditions (21% O2). Using a murine model of critical limb ischemia, platelet activity was increased even 2 weeks postsurgery compared with sham surgery mice. This effect was partly inhibited in platelet-specific ERK5 (extracellular regulated protein kinase 5) knockout mice. CONCLUSIONS: These findings suggest that ischemic disease changes the platelet phenotype and alters platelet agonist responses because of changes in the expression of signal transduction pathway proteins. Platelet phenotype and function should, therefore, be better characterized in ischemic and hypoxic diseases to understand the benefits and limitations of antiplatelet therapy.