Citations

Background The introduction of non–vitamin K antagonist oral anticoagulants has been a major advance for stroke prevention in atrial fibrillation; however, outcomes achieved in clinical trials may not translate to routine practice. We aimed to evaluate the effectiveness and safety of dabigatran, rivaroxaban, and apixaban by comparing each agent with warfarin. Methods and Results Using a large US insurance database, we identified privately insured and Medicare Advantage patients with nonvalvular atrial fibrillation who were users of apixaban, dabigatran, rivaroxaban, or warfarin between October 1, 2010, and June 30, 2015. We created 3 matched cohorts using 1:1 propensity score matching: apixaban versus warfarin (n=15 390), dabigatran versus warfarin (n=28 614), and rivaroxaban versus warfarin (n=32 350). Using Cox proportional hazards regression, we found that for stroke or systemic embolism, apixaban was associated with lower risk (hazard ratio [ HR ] 0.67, 95% CI 0.46–0.98, P =0.04), but dabigatran and rivaroxaban were associated with a similar risk (dabigatran: HR 0.98, 95% CI 0.76–1.26, P =0.98; rivaroxaban: HR 0.93, 95% CI 0.72–1.19, P =0.56). For major bleeding, apixaban and dabigatran were associated with lower risk (apixaban: HR 0.45, 95% CI 0.34–0.59, P <0.001; dabigatran: HR 0.79, 95% CI 0.67–0.94, P <0.01), and rivaroxaban was associated with a similar risk ( HR 1.04, 95% CI 0.90–1.20], P =0.60). All non–vitamin K antagonist oral anticoagulants were associated with a lower risk of intracranial bleeding. Conclusions In patients with nonvalvular atrial fibrillation, apixaban was associated with lower risks of both stroke and major bleeding, dabigatran was associated with similar risk of stroke but lower risk of major bleeding, and rivaroxaban was associated with similar risks of both stroke and major bleeding in comparison to warfarin.

Background Incidental mobile thrombi are commonly found on endovascular leads of cardiac implantable electronic devices ( CIED s). Transseptal puncture for catheter ablation of arrhythmia poses a risk for paradoxical embolism. We examined risk of ischemic stroke, transient ischemic attack ( TIA ), or systemic embolism after transseptal ablation in patients with and without CIED s. Methods and Results Using a national administrative claims database, 31 720 patients who underwent a transseptal catheter ablation between January 2004 and September 2014 were identified. Two propensity‐matched cohorts were created by matching demographic variables, administrative variables, Charlson Comorbidity Index, CHA 2 DS 2 ‐Vasc score, and year and indication for ablation (5533 and 11 300 patients with and without CIED s). Incidence rates and Cox proportional hazards models were used to estimate risk of ischemic stroke, TIA , or systemic embolism for patients with and without CIED s. Impact of oral anticoagulation ( OAC ) use on the endpoint was examined. Over a mean follow‐up of 2.1 years, the incidence of the combined endpoint was 1.9 per 100 person‐years in patients with CIED s and 1.5 per 100 person‐years in patients without CIED s ( P =0.03). Among patients not on OAC , presence of a cardiac device was associated with an increased risk (hazard ratio [ HR ], 1.71 [1.24–2.35]; P <0.01), whereas there was no association noted among patients treated with OAC ( HR , 0.98 [0.75–1.28]). Conclusion CIED s are associated with an increased risk of stroke, TIA , or systemic embolism after transseptal ablation, but this risk is attenuated with postablation OAC use. Role of anticoagulation post‐transseptal ablation in patients with CIED warrants further investigation.

Background: Quality measures are now commonplace and are increasingly tied to financial incentives. We reviewed the existing quality measures that address the upper limb and tested the null hypothesis that structure (capacity to deliver care), process (appropriate care), and outcome (the result of care) measures are equally represented. Methods: We systematically reviewed MEDLINE/PubMed, Embase, Google Scholar, the American Academy of Orthopaedic Surgeons Clinical Practice Guidelines, the National Quality Forum, the Agency for Healthcare Research and Quality, and the Physician Quality Reporting System for quality measures addressing upper limb surgery. Measures were characterized as structure, process, or outcome measures and were categorized according to their developer and their National Strategy for Quality Improvement in Health Care (National Quality Strategy) priority as articulated by the U.S. Department of Health & Human Services. Results: We identified 134 quality measures addressing the upper limb: 131 (98%) process and three (2%) outcome measures. The majority of the process measures address the National Quality Strategy priority of effective clinical care (90%), with the remainder addressing communication and care coordination (5%), person and caregiver-centered experience and outcomes (4%), and community/population health (1%). Conclusions: Our review identified opportunities to develop more measures in the structure and outcome domains as well as measures addressing patient and family engagement, public health, safety, care coordination, and efficient use of resources. The most common existing measures—process measures addressing care—might not be the best measures of upper limb surgery quality given the relative lack of evidence for their use in care improvement.

Background In comparison to warfarin, non–vitamin K antagonist oral anticoagulants ( NOAC s) have the advantages of ease of dosing, fewer drug interactions, and lack of need for ongoing monitoring. We sought to evaluate whether these advantages translate to improved adherence and whether adherence is associated with improved outcomes in patients with atrial fibrillation. Methods and Results We performed a retrospective cohort analysis by using a large US commercial insurance database to identify 64 661 patients with atrial fibrillation who initiated warfarin, dabigatran, rivaroxaban, or apixaban treatment between November 1, 2010, and December 31, 2014. During a median of 1.1 y of follow‐up, 47.5% of NOAC patients had a proportion of days covered of ≥80%, compared with 40.2% in warfarin patients ( P <0.001). Patients with CHA 2 DS 2 ‐ VAS c (risk based on the presence of congestive heart failure, hypertension age 65–74 y, age ≥75 y, diabetes mellitus, prior stroke or transient ischemic attack, vascular disease, sex category) score ≥4 were at increased risk of stroke when they were not taking anticoagulation ≥1 month versus <1 week (1–3 months: hazard ratio [ HR ] 1.96, 3–6 months: HR 2.64, ≥6 months: HR 3.66; all P <0.001). Patients with CHA 2 DS 2 ‐ VAS c score 2 or 3 were at increased risk of stroke when they were not taking anticoagulation ≥6 months ( HR 2.73, P <0.001). In these patients with CHA 2 DS 2 ‐ VAS c score ≥2, nonadherence was not associated with intracranial hemorrhage. Among patients with CHA 2 DS 2 ‐ VAS c score 0 or 1, time not taking anticoagulation was not associated with stroke, but not taking anticoagulation ≥3 months was associated with a significant reduction of bleeding. Conclusions Adherence to anticoagulation is poor in practice and may be modestly improved with NOAC s. Adherence to therapy appears to be most important in patients with CHA 2 DS 2 ‐ VAS c score ≥2, whereas the benefits of anticoagulation may not outweigh the harms in patients with CHA 2 DS 2 ‐ VAS c score 0 or 1.

ABSTRACT Understanding how some HIV-infected cells resist the cytotoxicity of HIV replication is crucial to enabling HIV cure efforts. HIV killing of CD4 T cells that replicate HIV can involve HIV protease-mediated cleavage of procaspase 8 to generate a fragment (Casp8p41) that directly binds and activates the mitochondrial proapoptotic protein BAK. Here, we demonstrate that Casp8p41 also binds with nanomolar affinity to the antiapoptotic protein Bcl-2, which sequesters Casp8p41 and prevents apoptosis. Further, we show that central memory CD4 T cells (T CM ) from HIV-infected individuals have heightened expression of BCL-2 relative to procaspase 8, possibly explaining the persistence of HIV-infected T CM despite generation of Casp8p41. Consistent with this hypothesis, the selective BCL-2 antagonist venetoclax induced minimal killing of uninfected CD4 T cells but markedly increased the death of CD4 T cells and diminished cell-associated HIV DNA when CD4 T cells from antiretroviral therapy (ART)-suppressed HIV patients were induced with αCD3/αCD28 to reactivate HIV ex vivo . Thus, priming CD4 T cells from ART suppressed HIV patients with a BCL-2 antagonist, followed by HIV reactivation, achieves reductions in cell-associated HIV DNA, whereas HIV reactivation alone does not. IMPORTANCE HIV infection is incurable due to a long-lived reservoir of HIV + memory CD4 T cells, and no clinically relevant interventions have been identified that reduce the number of these HIV DNA-containing cells. Since postintegration HIV replication can result in HIV protease generation of Casp8p41, which activates BAK, causing infected CD4 T cell death, we sought to determine whether this occurs in memory CD4 T cells. Here, we demonstrate that memory CD4 T cells can generate Casp8p41 and yet are intrinsically resistant to death induced by diverse stimuli, including Casp8p41. Furthermore, BCL-2 expression is relatively increased in these cells and directly binds and inhibits Casp8p41's proapoptotic effects. Antagonizing BCL-2 with venetoclax derepresses this antagonism, resulting in death, preferentially in HIV DNA containing cells, since only these cells generate Casp8p41. Thus, BCL-2 antagonism is a clinically relevant intervention with the potential to reduce HIV reservoir size in patients.

Abstract Histiocytic neoplasms are clonal, hematopoietic disorders characterized by an accumulation of abnormal, monocyte-derived dendritic cells or macrophages in Langerhans cell histiocytosis (LCH) and non-Langerhans cell histiocytosis (non-LCH), respectively. The discovery of BRAFV600E mutations in approximately 50% of these patients provided the first molecular therapeutic target in histiocytosis. However, recurrent driving mutations in the majority of patients with BRAFV600E–wild-type non-LCH are unknown, and recurrent cooperating mutations in non-MAP kinase pathways are undefined for the histiocytic neoplasms. Through combined whole-exome and transcriptome sequencing, we identified recurrent kinase fusions involving BRAF, ALK, and NTRK1, as well as recurrent, activating MAP2K1 and ARAF mutations in patients with BRAFV600E–wild-type non-LCH. In addition to MAP kinase pathway lesions, recurrently altered genes involving diverse cellular pathways were identified. Treatment of patients with MAP2K1- and ARAF-mutated non-LCH using MEK and RAF inhibitors, respectively, resulted in clinical efficacy, demonstrating the importance of detecting and targeting diverse kinase alterations in these disorders. Significance: We provide the first description of kinase fusions in systemic histiocytic neoplasms and activating ARAF and MAP2K1 mutations in non-Langerhans histiocytic neoplasms. Refractory patients with MAP2K1- and ARAF-mutant histiocytoses had clinical responses to MEK inhibition and sorafenib, respectively, highlighting the importance of comprehensive genomic analysis of these disorders. Cancer Discov; 6(2); 154–65. ©2015 AACR. This article is highlighted in the In This Issue feature, p. 109

Background There is significant practice variation in oral anticoagulation ( OAC ) use following catheter ablation for atrial fibrillation. It is not clear whether the risk of cardioembolism increases after discontinuation of OAC following catheter ablation. Methods and Results We identified 6886 patients within a large national administrative claims database who underwent catheter ablation for atrial fibrillation between January 1, 2005, and September 30, 2014. We assessed the effect of time off of OAC by CHA 2 DS 2 ‐ VAS c score (after adjusting for other comorbidities) on risk of cardioembolism, using Cox proportional hazards models. There was an increase in the use of non–vitamin K OAC after ablation from 0% in 2005 to 69.8% in 2014. OAC discontinuation was high, with only 60.5% and 31.3% of patients remaining on OAC at 3 and 12 months, respectively. The rate of discontinuation was higher in low‐risk patients (82% versus 62.5% at 12 months for CHA 2 DS 2 ‐ VAS c 0–1 versus ≥2, respectively; P <0.001). Stroke occurred in 1.4% of patients with CHA 2 DS 2 ‐ VAS c ≥2 and 0.3% of those with CHA 2 DS 2 ‐ VAS c 0 or 1 over the study follow‐up. The risk of cardioembolism in the first 3 months after ablation was increased among those with any time off OAC (hazard ratio 8.06 [95% CI 1.53–42.3], P <0.05). The risk of cardioembolism beyond 3 months was increased with OAC discontinuation among high‐risk patients (hazard ratio 2.48 [95% CI 1.11–5.52], P <0.05) but not low‐risk patients. Conclusion The overall risk of stroke in postablation patients is low; however, OAC discontinuation after ablation is common and is associated with increased risk of cardioembolism for all patients within the first 3 months and for high‐risk patients in the long term. Continuing OAC for at least 3 months in all patients and indefinitely in high‐risk patients appears to be the safest strategy.