A targeted educational intervention increases oral anticoagulation rates in high-risk atrial fibrillation patients.

Background: Anticoagulation is the cornerstone of atrial fibrillation (AF) management for stroke prevention. Recently, we showed that oral anticoagulation (OAC) rates of AF patients in a large U.S. multispecialty health system are >80%. Objective: The purpose of this study was to improve OAC rates in AF patients via an educational intervention targeted to primary care providers with low OAC rates. Methods: Primary care clinicians were stratified by proportions of their AF patients at elevated stroke risk not taking anticoagulation medication. Clinicians with the lowest rates of anticoagulation were assigned to a target group receiving an educational program consisting of E-mail messaging summarizing anticoagulation guidelines. All other clinicians were assigned to a comparison group (CG). Data from a 6-month lead-in phase were compared with a 6-month follow-up period to determine whether the proportion of AF patients treated with OACs had changed. Results: Of the 141 primary care clinicians with patients who met the inclusion criteria, 36 (25.53%) were assigned to the educational group (EG) and 105 (74.47%) to the CG. At baseline, there was a significant difference in percent of high-risk AF patients who were untreated in the EG (20.65%) compared to the high-risk patients who were untreated in the CG (13.64%; P = .001). After the educational intervention, high-risk AF patients without anticoagulation decreased in both EG (15.47%; P = .047) and CG (10.14%; P = .07), with greater absolute reduction in the EG (5.19% vs 3.50%). Conclusion: A targeted education program was associated with increased anticoagulation rates for AF patients at high risk for stroke.

High rates of oral anticoagulation in atrial fibrillation patients observed in a large multi-specialty health system in the Northeast.

BACKGROUND: Anticoagulation is a cornerstone in atrial fibrillation (AF) management for stroke prevention. Studies showed that oral anticoagulants (OAC), previously limited to warfarin, were underused. Recently, non-vitamin K oral anticoagulants (NOACs) have seen widespread adoption, but it has not been well studied whether there has been a subsequent increase in OAC usage in AF patients. METHODS: We quantified OAC rates in AF patients in a large multispecialty health system in the Northeast United States. A total of 351,795 patients seen in the network over the preceding 18 months were reviewed. RESULTS: Of these patients, 8727 (2.5%) carried a diagnosis of AF, and, of the 6933 patients with a CHA2DS2-VASc score of 2 or higher, 5576 (80.4%) had an OAC listed as an active medication or had received a left atrial appendage occlusion device. Of the 6605 patients treated with an OAC, 5308 (80.4%) were treated with a NOAC and 1295 (19.6%) were prescribed warfarin. A higher percentage of patients with CHA2DS2-VASc ≥ 2 who had seen a cardiologist were treated with an OAC vs. those who had not seen a cardiologist in the prior 18 months (83.95% vs. 67.43%, p < 0.01). CONCLUSIONS: We show dramatically increased OAC usage among patients with AF and that NOACs comprise the large majority of OACs compared with previous studies. This suggests an association between widespread adoption of NOACs and increased oral anticoagulation rates. Future directions include assessing barriers to oral anticoagulation and developing interventions to reduce disparity in OAC use between clinics.

Preclinical Evaluation of Foamy Virus Vector-Mediated Gene Addition in Human Hematopoietic Stem/Progenitor Cells for Correction of Leukocyte Adhesion Deficiency Type 1.

Ex vivo gene therapy procedures targeting hematopoietic stem and progenitor cells (HSPCs) predominantly utilize lentivirus-based vectors for gene transfer. We provide the first pre-clinical evidence of the therapeutic utility of a foamy virus vector (FVV) for the genetic correction of human leukocyte adhesion deficiency type 1 (LAD-1), an inherited primary immunodeficiency resulting from mutation of the ß2 integrin common chain, CD18. CD34+ HSPCs isolated from a severely affected LAD-1 patient were transduced under a current good manufacturing practice-compatible protocol with FVV harboring a therapeutic CD18 transgene. LAD-1-associated cellular chemotactic defects were ameliorated in transgene-positive, myeloid-differentiated LAD-1 cells assayed in response to a strong neutrophil chemoattractant in vitro. Xenotransplantation of vector-transduced LAD-1 HSPCs in immunodeficient (NSG) mice resulted in long-term (∼5 months) human cell engraftment within murine bone marrow. Moreover, engrafted LAD-1 myeloid cells displayed in vivo levels of transgene marking previously reported to ameliorate the LAD-1 phenotype in a large animal model of the disease. Vector insertion site analysis revealed a favorable vector integration profile with no overt evidence of genotoxicity. These results coupled with the unique biological features of wild-type foamy virus support the development of FVVs for ex vivo gene therapy of LAD-1.

Loss of adenomatous poliposis coli-α3 integrin interaction promotes endothelial apoptosis in mice and humans.

RATIONALE: Pulmonary hypertension (PH) is characterized by progressive elevation in pulmonary pressure and loss of small pulmonary arteries. As bone morphogenetic proteins promote pulmonary angiogenesis by recruiting the Wnt/ß-catenin pathway, we proposed that ß-catenin activation could reduce loss and induce regeneration of small pulmonary arteries (PAs) and attenuate PH. OBJECTIVE: This study aims to establish the role of ß-catenin in protecting the pulmonary endothelium and stimulating compensatory angiogenesis after injury. METHODS AND RESULTS: To assess the impact of ß-catenin activation on chronic hypoxia-induced PH, we used the adenomatous polyposis coli (Apc(Min/+)) mouse, where reduced APC causes constitutive ß-catenin elevation. Surprisingly, hypoxic Apc(Min/+) mice displayed greater PH and small PA loss compared with control C57Bl6J littermates. PA endothelial cells isolated from Apc(Min/+) demonstrated reduced survival and angiogenic responses along with a profound reduction in adhesion to laminin. The mechanism involved failure of APC to interact with the cytoplasmic domain of the α3 integrin, to stabilize focal adhesions and activate integrin-linked kinase-1 and phospho Akt. We found that PA endothelial cells from lungs of patients with idiopathic PH have reduced APC expression, decreased adhesion to laminin, and impaired vascular tube formation. These defects were corrected in the cultured cells by transfection of APC. CONCLUSIONS: We show that APC is integral to PA endothelial cells adhesion and survival and is reduced in PA endothelial cells from PH patient lungs. The data suggest that decreased APC may be a cause of increased risk or severity of PH in genetically susceptible individuals.