Apixaban Discontinuation for Invasive Or major Surgical procedures (ADIOS): A prospective cohort study.

Background: Apixaban pharmacokinetic properties and some clinical reports suggest cessation 48 hours prior to surgery is safe, but this has not been demonstrated in a naturalistic setting. We sought to measure the residual apixaban exposure in patients who had apixaban held as part of standard of care perioperative management. Methods: This was a prospective, observational study of patients in whom apixaban plasma concentration and anti-Xa activity were measured while at steady state apixaban dosing and again immediately prior to surgery. Clinical management of cessation and resumption of apixaban was at the discretion of the treating physician. Results: Paired blood samples were provided by 111 patients. Ninety-four percent (104/111) of patients had measured apixaban concentrations of ⩽ 30 ng/mL. Only one patient had a value > 50 ng/mL. The median time between the self-reported last dose and presurgery blood sampling was 76 hours (range 32-158) for those who achieved concentrations ⩽ 30 ng/mL and 59 hours (range 49-86) for those > 30 ng/mL. Measured anti-Xa activity correlated well with apixaban exposure. Clinically significant nonmajor bleeding was reported in one patient at 1 week postsurgery. There was one venous thromboembolic event and one stroke in the perioperative period. Conclusion: In a naturalistic setting with a heterogeneous patient population, apixaban discontinuation for at least 48 hours before a procedure resulted in a clinically insignificant degree of anticoagulation prior to a surgical procedure. ClinicalTrials.gov Identifier: NCT02935751.

In vivo electroporation of constitutively expressed HIF-1α plasmid DNA improves neovascularization in a mouse model of limb ischemia.

OBJECTIVE: Hypoxia-inducible factor-1 alpha (HIF-1α) is a transcription factor that stimulates angiogenesis during tissue ischemia. In vivo electroporation (EP) enhances tissue DNA transfection. We hypothesized that in vivo EP of plasmid DNA encoding a constitutively expressed HIF-1α gene enhances neovascularization compared with intramuscular (IM) injection alone. METHODS: Left femoral artery ligation was performed in mice assigned to three groups: (1) HIF-EP (n = 13); (2) HIF-IM (n = 14); and (3) empty plasmid (pVAX)-EP (n = 12). A single dose of HIF-1α or pVAX DNA (20 µL of 5 µg/µL each) was injected into the ischemic adductor muscle followed by EP (groups one and three). Mice in group two received IM injection of HIF-1α plasmid DNA alone. From preligation to days 0, 3, 7, 14, and 21 postligation, limb perfusion recovery quantified by laser Doppler perfusion imager, limb function, and limb necrosis were measured. On day 21, the surviving mice (4-5 per group) were sacrificed and adductor muscle tissues stained for necrosis using hematoxylin and eosin, capillary density (anti-CD31 antibodies), and collateral vessels via anti-α-smooth muscle actin antibodies. RESULTS: In vivo EP of HIF-1α DNA significantly improved limb perfusion (HIF-EP: 1.03 ± 0.15 vs HIF-IM: 0.78 ± 0.064; P < .05, vs pVAX-EP: 0.41 ± 0.019; P < .001), limb functional recovery (HIF-EP: 3.5 ± 0.58 vs HIF-IM, 2.4 ± 1.14; P < .05, vs pVAX-EP: 2.4 ± 1.14; P < .001), and limb autoamputation on day 21 (HIF-EP: 77% ± 12% vs HIF-IM: 43% ± 14%; P < .05 vs pVAX-EP: 17% ± 11%; P < .01). Adductor muscle tissue necrosis decreased (HIF-EP: 20.7% ± 1.75% vs HIF-IM: 44% ± 3.73; P < .001, vs pVAX-EP: 60.05% ± 2.17%; P < .0001), capillary density increased (HIF-EP: 96.83 ± 5.72 vessels/high-powered field [hpf] vs HIF-IM: 62.87 ± 2.0 vessels/hpf; P < .001, vs pVAX-EP: 39.37 ± 2.76 vessels/hpf; P < .0001), collateral vessel formation increased (HI-EP: 76.33 ± 1.94 vessels/hpf vs HIF-IM: 37.5 ± 1.56 vessels/hpf; P < .0001, vs pVAX-EP: 18.5 ± 1.34 vessels/hpf; P < .00001), and the vessels were larger (HIF-EP: 15,521.67 ± 1298.16 µm(2) vs HIF-IM: 7788.87 ± 392.04 µm(2); P < .001 vs pVAX-EP: 4640.25 ± 614.01 µm(2); P < .0001). CONCLUSIONS: In vivo EP-mediated delivery of HIF-1α plasmid DNA improves neovascularization in a mouse model of limb ischemia and is a potentially suitable nonviral, noninvasive intervention to facilitate therapeutic angiogenesis in critical limb ischemia.

Therapeutic angiogenesis in critical limb ischemia.

Critical limb ischemia (CLI) is a severe form of peripheral artery disease associated with high morbidity and mortality. The primary therapeutic goals in treating CLI are to reduce the risk of adverse cardiovascular events, relieve ischemic pain, heal ulcers, prevent major amputation, and improve quality of life (QoL) and survival. These goals may be achieved by medical therapy, endovascular intervention, open surgery, or amputation and require a multidisciplinary approach including pain management, wound care, risk factors reduction, and treatment of comorbidities. No-option patients are potential candidates for the novel angiogenic therapies. The application of genetic, molecular, and cellular-based modalities, the so-called therapeutic angiogenesis, in the treatment of arterial obstructive diseases has not shown consistent efficacy. This article summarizes the current status related to the management of patients with CLI and discusses the current findings of the emerging modalities for therapeutic angiogenesis.

Targets and delivery methods for therapeutic angiogenesis in peripheral artery disease.

Therapeutic angiogenesis utilizing genetic and cellular modalities in the treatment of arterial obstructive diseases continues to evolve. This is, in part, because the mechanism of vasculogenesis, angiogenesis, and arteriogenesis (the three processes by which the body responds to obstruction of large conduit arteries) is a complex process that is still under investigation. To date, the majority of human trials utilizing molecular, genetic, and cellular modalities for therapeutic angiogenesis in the treatment of peripheral artery disease (PAD) have not shown efficacy. Consequently, the current available knowledge is yet to be translated into novel therapeutic approaches for the treatment of PAD. The aim of this review is to discuss relevant scientific and clinical advances in therapeutic angiogenesis and their potential application in the treatment of ischemic diseases of the peripheral arteries. Additionally, this review article discusses past and recent developments, such as some unconventional approaches that have the potential to be applied as therapeutic targets. The article also includes advances in the delivery of genetic, cellular, and bioactive endothelial growth factors.