Assessment of Temporary Warfarin Reversal in Patients With Left Ventricular Assist Devices: the KVAD Study.

BACKGROUND: Patients with left ventricular assist devices (LVADs) require interruption of warfarin for invasive procedures, but parenteral bridging is associated with many complications. Four-factor prothrombin complex concentrate (4F-PCC) can temporarily restore hemostasis in patients undergoing anticoagulation with warfarin. OBJECTIVES: This pilot study evaluated the strategy of using variable-dose 4F-PCC to immediately and temporarily reverse warfarin before invasive procedures without holding warfarin in patients with LVADs. The duration of effect of 4F-PCC on factor levels and time to reestablish therapeutic anticoagulation post procedure were assessed. METHODS: Adult patients with LVADs and planned invasive procedures were enrolled from a single center. Warfarin was continued uninterrupted. The 4F-PCC dose administered immediately pre-procedure was based on study protocol. International normalized ratio (INR)- and vitamin K-dependent factor levels were collected before and during the 48 hours after 4F-PCC administration. The use of parenteral bridging, International Society for Thrombosis and Haemostasis major and clinically relevant nonmajor bleeding (CRNMB) and thromboembolic events at 7 and 30 days were collected. RESULTS: In 21 episodes of 4F-PCC reversal, median baseline INR was 2.7 (IQR 2.2-3.2). The median dosage of 4F-PCC administered was 1794 units (IQR 1536-2130). At 24 and 48 hours post 4F-PCC administration, median INRs were 1.8 (IQR 1.7-2.0) and 2.0 (IQR 1.9-2.4). Two patients required postoperative bridging. One patient experienced major bleeding within 72 hours, and 2 experienced CRNMB within 30 days. There were no thromboembolic events. Baseline and post 4F-PCC vitamin K-dependent factor levels corresponded with changes in INR values. The median time to achieve therapeutic INR post-procedure was 2.5 days (IQR, 1-4). CONCLUSION: Administration of 4F-PCC for temporary reversal of warfarin for invasive procedures in patients with LVADs allowed for continued warfarin dosing with minimal use of post-intervention bridging, limited bleeding and no thromboembolic events.

Four factor prothrombin complex concentrate for warfarin reversal in patients with left ventricular assist devices.

Continuous flow left ventricular assist devices (CF-LVAD) require therapeutic anticoagulation which is often interrupted for procedures or bleeding. Prior to the availability of four factor prothrombin complex concentrate (4F-PCC) in the United States, warfarin was held and its effects reversed by vitamin K or fresh frozen plasma. We evaluated the use of 4F-PCC for temporary warfarin reversal in patients with CF-LVADs and assessed outcomes. This analysis is a retrospective study of CF-LVAD patients who received 4F-PCC for warfarin reversal in the setting of bleeding or need for urgent or elective procedures. Primary outcome assessments included feasibility of administration in elective versus emergent situations, safety measured as incidence of thrombotic events, and change in INR after administration. In total, 37 CF-LVAD patients received 49 4F-PCC administrations. The average 4F-PCC dose was 1842 units (range 518-4292 units), or 22 units/kg (range 5.8-58 units/kg). 4F-PCC significantly decreased the mean INR from 2.9 to 1.7 (p < 0.0001) in 47 of 49 administrations; two patients did not have post infusion INR testing. No cases of new confirmed or suspected pump thrombosis, stroke, venous thromboembolism, arterial thrombosis, or myocardial infarction were observed within 30 days of administration of 4F-PCC. 4F-PCC administration for temporary warfarin reversal was demonstrated to be feasible, effective, and, safe in CF-LVAD patients and judged to be 96% effective in patients for whom data were available. We observed no thrombotic events attributed to use of 4F-PCC.

Development of an Outpatient Guideline for Optimal Anticoagulation Bridging in Patients With Durable Mechanical Circulatory Support.

Patients with durable mechanical circulatory support are at increased risk of thromboembolic and bleeding complications. Current guidelines recommend that these patients receive chronic anticoagulation with warfarin to maintain a target international normalized ratio (INR) as specified by device manufacturers. Limited data exist regarding management of subtherapeutic INRs in this setting. To standardize clinical practice at our institution, we assembled a multidisciplinary task force including members from various specialties to develop a guideline for managing subtherapeutic INRs that incorporates published data and expert opinion. In this article, we present our clinical practice guideline as a decision support tool to aid clinicians in developing a consistent strategy for managing subtherapeutic INRs and for safely bridging anticoagulation in patients receiving mechanical circulatory support.

Insulin-like growth factor-1 receptor expression masks the antiinflammatory and glucose uptake capacity of insulin in vascular smooth muscle cells.

OBJECTIVE: Insulin resistance of vascular smooth muscle cells (VSMCs) has been linked to accelerated atherosclerosis in diabetes; however, the effects of insulin on VSMCs remain controversial. Most VSMC insulin receptors are sequestered into insulin-insensitive hybrids with insulin-like growth factor-1 receptors (IGF1Rs). Thus we hypothesized that regulation of IGF1R expression may impact cellular insulin sensitivity. METHODS AND RESULTS: IGF1R expression was increased in aortas from diabetic mice. IGF1R overexpression in VSMCs impaired insulin-induced Akt phosphorylation. Conversely, IGF1R downregulation by siRNA allowed assembly of insulin holoreceptors, enhanced insulin-induced phosphorylation of its receptor, Akt, Erk1/2, and further augmented insulin-induced glucose uptake. IGF1R downregulation uncovered an insulin-induced reduction in activation of NF-kappaB and inhibition of MCP-1 upregulation in response to TNF-alpha. CONCLUSIONS: Downregulation of IGF1R increases the fraction of insulin receptors organized in holoreceptors, which leads to enhanced insulin signaling and unmasks potential antiinflammatory properties of insulin in VSMCs. Therefore, IGF1R, which is susceptible to feedback regulation by its own ligand, may represent a novel target for interventions designed to treat insulin resistance in the vasculature.

Mechanisms of vascular smooth muscle NADPH oxidase 1 (Nox1) contribution to injury-induced neointimal formation.

OBJECTIVE: Vascular NADPH oxidases (Noxes) have been implicated in cardiovascular diseases; however, the importance of individual Nox homologues remains unclear. Here, the role of the vascular smooth muscle cell (VSMC) Nox1 in neointima formation was studied using genetically modified animal models. METHODS AND RESULTS: Wire injury-induced neointima formation in the femoral artery, along with proliferation and apoptosis, was reduced in Nox1(y/-) mice, but there was little difference in Tg(SMCnox1) mice compared with wild-type (WT) mice. Proliferation and migration were reduced in cultured Nox1(y/-) VSMCs and increased in Tg(SMCnox1) cells. Tg(SMCnox1) cells exhibited increased fibronectin secretion, but neither collagen I production nor cell adhesion was affected by alteration of Nox1. Using antibody microarray and Western blotting analysis, increased cofilin phosphorylation and mDia1 expression and decreased PAK1 expression were detected in Nox1(y/-) cells. Overexpression of S3A, a constitutively active cofilin mutant, partially recovered reduced migration of Nox1(y/-) cells, suggesting that reduction in cofilin activity contributes to impaired migration of Nox1(y/-) VSMCs. CONCLUSIONS: These results indicate that Nox1 plays a critical role in neointima formation by mediating VSMC migration, proliferation, and extracellular matrix production, and that cofilin is a major effector of Nox1-mediated migration. Inhibition of Nox1 may be an efficient strategy to suppress neointimal formation.