Technologies and Computational Analysis Strategies for CRISPR Applications.

The CRISPR-Cas system offers a programmable platform for eukaryotic genome and epigenome editing. The ability to perform targeted genetic and epigenetic perturbations enables researchers to perform a variety of tasks, ranging from investigating questions in basic biology to potentially developing novel therapeutics for the treatment of disease. While CRISPR systems have been engineered to target DNA and RNA with increased precision, efficiency, and flexibility, assays to identify off-target editing are becoming more comprehensive and sensitive. Furthermore, techniques to perform high-throughput genome and epigenome editing can be paired with a variety of readouts and are uncovering important cellular functions and mechanisms. These technological advances drive and are driven by accompanying computational approaches. Here, we briefly present available CRISPR technologies and review key computational advances and considerations for various CRISPR applications. In particular, we focus on the analysis of on- and off-target editing and CRISPR pooled screen data.

Author Correction: Predictable and precise template-free CRISPR editing of pathogenic variants.

In this Article, a data processing error affected Fig. 3e and Extended Data Table 2; these errors have been corrected online.

Comparative Effectiveness of Left Atrial Appendage Occlusion Versus Oral Anticoagulation by Sex.

BACKGROUND: The comparative real-world outcomes of older patients with atrial fibrillation (AF) treated with anticoagulation compared with left atrial appendage occlusion (LAAO) may be different from those in clinical trials because of differences in anticoagulation strategies and patient demographics, including a greater proportion of women. We sought to compare real-world outcomes between older patients with AF treated with anticoagulation and those treated with LAAO by sex. METHODS: Using Medicare claims data from 2015 to 2019, we identified LAAO-eligible beneficiaries and divided them into sex subgroups. Patients receiving LAAO were matched 1:1 to those receiving anticoagulation alone through propensity score matching. The risks of mortality, stroke or systemic embolism, and bleeding were compared between matched groups with adjustment for potential confounding characteristics in Cox proportional hazards models. RESULTS: Among women, 4085 LAAO recipients were matched 1:1 to those receiving anticoagulation; among men, 5378 LAAO recipients were similarly matched. LAAO was associated with a significant reduction in the risk of mortality for women and men (hazard ratio [HR], 0.509 [95% CI, 0.447-0.580]; and HR, 0.541 [95% CI, 0.487-0.601], respectively; P<0.0001), with a similar finding for stroke or systemic embolism (HR, 0.655 [95% CI, 0.555-0.772]; and HR, 0.649 [95% CI, 0.552-0.762], respectively; P<0.0001). Bleeding risk was significantly greater in LAAO recipients early after implantation but lower after the 6-week periprocedural period for women and men (HR, 0.772 [95% CI, 0.676-0.882]; and HR, 0.881 [95% CI, 0.784-0.989], respectively; P<0.05). CONCLUSIONS: In a real-world population of older Medicare beneficiaries with AF, compared with anticoagulation, LAAO was associated with a reduction in the risk of death, stroke, and long-term bleeding among women and men. These findings should be incorporated into shared decision-making with patients considering strategies for reduction in AF-related stroke.

Stroke Prevention in Atrial Fibrillation: Our Current Failures and Required Research.

Nonvalvular atrial fibrillation is a common rhythm disorder of middle-aged to older adults that can cause ischemic strokes and systemic embolism. Lifelong use of oral anticoagulants reduces the risk of these ischemic events but increases the risk of major and clinically relevant hemorrhages. These medications also require strict compliance for efficacy, and they have nontrivial failure rates in higher-risk patients. Left atrial appendage closure is a nonpharmacological method to prevent ischemic strokes in atrial fibrillation without the need for lifelong anticoagulant use, but this procedure has the potential for complications and residual embolic events. This workshop of the Roundtable of Academia and Industry for Stroke Prevention discussed future research needed to further decrease the ischemic and hemorrhagic risks among patients with atrial fibrillation. A direct thrombin inhibitor, factor Xa inhibitors, and left atrial appendage closure are FDA-approved approaches whereas factor XIa inhibitors are currently being studied in phase 3 randomized controlled trials for stroke prevention. The benefits, risks, and shortcomings of these treatments and future research required in different high-risk patient populations are reviewed in this consensus statement.

Impact of artificial intelligence arrhythmia mapping on time to first ablation, procedure duration, and fluoroscopy use.

INTRODUCTION: Artificial intelligence (AI) ECG arrhythmia mapping provides arrhythmia source localization using 12-lead ECG data; whether this information impacts procedural efficiency is unknown. We performed a retrospective, case-control study to evaluate the hypothesis that AI ECG mapping may reduce time to ablation, procedural duration, and fluoroscopy. MATERIALS AND METHODS: Cases in which system output was used were retrospectively enrolled according to IRB-approved protocols at each site. Matched control cases were enrolled in reverse chronological order beginning on the last day for which the technology was unavailable. Controls were matched based upon physician, institution, arrhythmia, and a predetermined complexity rating. Procedural metrics, fluoroscopy data, and clinical outcomes were assessed from time-stamped medical records. RESULTS: The study group consisted of 28 patients (age 65 ± 11 years, 46% female, left atrial dimension 4.1 ± 0.9 cm, LVEF 50 ± 18%) and was similar to 28 controls. The most common arrhythmia types were atrial fibrillation (n = 10), premature ventricular complexes (n = 8), and ventricular tachycardia (n = 6). Use of the system was associated with a 19.0% reduction in time to ablation (133 ± 48 vs. 165 ± 49 min, p = 0.02), a 22.6% reduction in procedure duration (233 ± 51 vs. 301 ± 83 min, p < 0.001), and a 43.7% reduction in fluoroscopy (18.7 ± 13.3 vs. 33.2 ± 18.0 min, p < 0.001) versus controls. At 6 months follow-up, arrhythmia-free survival was 73.5% in the study group and 63.3% in the control group (p = 0.56). CONCLUSION: Use of forward-solution AI ECG mapping is associated with reductions in time to first ablation, procedure duration, and fluoroscopy without an adverse impact on procedure outcomes or complications.

Predictable and precise template-free CRISPR editing of pathogenic variants.

Following Cas9 cleavage, DNA repair without a donor template is generally considered stochastic, heterogeneous and impractical beyond gene disruption. Here, we show that template-free Cas9 editing is predictable and capable of precise repair to a predicted genotype, enabling correction of disease-associated mutations in humans. We constructed a library of 2,000 Cas9 guide RNAs paired with DNA target sites and trained inDelphi, a machine learning model that predicts genotypes and frequencies of 1- to 60-base-pair deletions and 1-base-pair insertions with high accuracy (r = 0.87) in five human and mouse cell lines. inDelphi predicts that 5-11% of Cas9 guide RNAs targeting the human genome are 'precise-50', yielding a single genotype comprising greater than or equal to 50% of all major editing products. We experimentally confirmed precise-50 insertions and deletions in 195 human disease-relevant alleles, including correction in primary patient-derived fibroblasts of pathogenic alleles to wild-type genotype for Hermansky-Pudlak syndrome and Menkes disease. This study establishes an approach for precise, template-free genome editing.

Combined atrial fibrillation ablation and left atrial appendage occlusion procedure in the United States: a propensity score matched analysis from 2016-2019 national readmission database.

AIMS: The safety and feasibility of combining percutaneous catheter ablation (CA) for atrial fibrillation with left atrial appendage occlusion (LAAO) as a single procedure in the USA have not been investigated. We analyzed the US National Readmission Database (NRD) to investigate the incidence of combined LAAO + CA and compare major adverse cardiovascular events (MACEs) with matched LAAO-only and CA-only patients. METHODS AND RESULTS: In this retrospective study from NRD data, we identified patients undergoing combined LAAO and CA procedures on the same day in the USA from 2016 to 2019. A 1:1 propensity score match was performed to identify patients undergoing LAAO-only and CA-only procedures. The number of LAAO + CA procedures increased from 28 (2016) to 119 (2019). LAAO + CA patients (n = 375, mean age 74 ± 9.2 years, 53.4% were males) had non-significant higher MACE (8.1%) when compared with LAAO-only (n = 407, 5.3%) or CA-only patients (n = 406, 7.4%), which was primarily driven by higher rate of pericardial effusion (4.3%). All-cause 30-day readmission rates among LAAO + CA patients (10.7%) were similar when compared with LAAO-only (12.7%) or CA-only (17.5%) patients. The most frequent primary reason for readmissions among LAAO + CA and LAAO-only cohorts was heart failure (24.6 and 31.5%, respectively), while among the CA-only cohort, it was paroxysmal atrial fibrillation (25.7%). CONCLUSION: We report an 63% annual growth (from 28 procedures) in combined LAAO and CA procedures in the USA. There were no significant difference in MACE and all-cause 30-day readmission rates among LAAO + CA patients compared with matched LAAO-only or CA-only patients.

In-hospital complications associated with pulmonary vein isolation with adjunctive lesions: the NCDR AFib Ablation Registry.

AIMS: No prior study has been adequately powered to evaluate real-world safety outcomes in those receiving adjunctive ablation lesions beyond pulmonary vein isolation (PVI). We sought to evaluate characteristics and in-hospital complications among patients undergoing PVI with and without adjunctive lesions. METHODS AND RESULTS: Patients in the National Cardiovascular Data Registry AFib Ablation Registry undergoing first-time atrial fibrillation (AF) ablation between 2016 and 2020 were identified and stratified into paroxysmal (PAF) and persistent AF, and separated into PVI only, PVI + cavotricuspid isthmus (CTI) ablation, and PVI + adjunctive (superior vena cava isolation, coronary sinus, vein of Marshall, atypical atrial flutter lines, other). Adjusted odds of adverse events were calculated using multivariable logistic regression. A total of 50 937 patients [PAF: 30 551 (60%), persistent AF: 20 386 (40%)] were included. Among those with PAF, there were no differences in the adjusted odds of complications between PVI + CTI or PVI + adjunctive when compared with PVI only. Among persistent AF, PVI + adjunctive was associated with a higher risk of any complication [3.0 vs. 4.5%, odds ratio (OR) 1.30, 95% confidence interval (CI) 1.07-1.58] and major complication (0.8 vs. 1.4%, OR 1.56, 95% CI 1.10-2.21), while no differences were observed in PVI + CTI compared with PVI only. Overall, there was high heterogeneity in adjunctive lesion type, and those receiving adjunctive lesions had a higher comorbidity burden. CONCLUSION: Additional CTI ablation was common without an increased risk of complications. Adjunctive lesions other than CTI are commonly performed in those with more comorbidities and were associated with an increased risk of complications in persistent AF, although the current analysis is limited by high heterogeneity in adjunctive lesion set type.

In vivo porcine characterization of atrial lesion safety and efficacy utilizing a circular pulsed-field ablation catheter including assessment of collateral damage to adjacent tissue in supratherapeutic ablation applications.

INTRODUCTION: Pulsed-field ablation (PFA), an ablative method that causes cell death by irreversible electroporation, has potential safety advantages over radiofrequency ablation and cryoablation. Pulmonary vein (PV) isolation was performed in a porcine model to characterize safety and performance of a novel, fully-integrated biphasic PFA system comprising a multi-channel generator, variable loop circular catheter, and integrated PFA mapping software module. METHODS: Eight healthy porcine subjects were included. To evaluate safety, multiple ablations were performed, including sites not generally targeted for therapeutic ablation, such as the right inferior PV lumen, right superior PV ostium, and adjacent to the esophagus and phrenic nerve. To evaluate the efficacy, animals were recovered, followed for 30(±3) days, then re-mapped. Gross pathological and histopathological examinations assessed procedural injuries, chronic thrombosis, tissue ablation, penetration depth, healing, and inflammatory response. RESULTS: All eight animals survived follow-up. PV narrowing was not observed acutely nor at follow-up, even when ablation was performed deep to the PV ostium. No injury was seen grossly or histologically in adjacent structures. All PVs were durably isolated, confirmed by bidirectional block at re-map procedure. Histological examination showed complete, transmural necrosis around the circumference of the ablated section of right PVs. CONCLUSION: This preclinical evaluation of a fully-integrated PFA system demonstrated effective and durable ablation of cardiac tissue and PV isolation without collateral damage to adjacent structures, even when ablation was performed in more extreme settings than those used therapeutically. Histological staining confirmed complete transmural cell necrosis around the circumference of the PV ostium at 30 days.

Association of heart failure with procedural complications and in-hospital outcomes from left atrial appendage occlusion device implantation in patients with atrial fibrillation: insights from the national inpatient sample of 62 980 procedures.

AIMS: To determine outcomes in atrial fibrillation (AF) patients undergoing percutaneous left atrial appendage occlusion (LAAO) with concomitant heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF). METHODS AND RESULTS: Data were extracted from National Inpatient Sample for calendar years 2015-2019. LAAO device implantations were identified on the basis of ICD-10-CM code of 02L73DK. The outcomes assessed in our study included complications, in-patient mortality, and resource utilization. A total of 62 980 LAAO device implantations were studied. HFpEF (14.4%, n = 9040) and HFrEF (11.2%, n = 7100) were associated with a higher prevalence of major complications and in-patient mortality in crude analysis. In the multivariate model adjusted for potential confounders, HFpEF and HFrEF were not associated with major complications [adjusted odds ratio (aOR) 1.04, 95% confidence interval (CI) 0.93-1.16 and aOR 1.07, 95% CI 0.95-1.21] or in-patient mortality (aOR 1.48, 95% CI 0.85-2.55 and aOR 1.26, 95% CI 0.67-2.38). HFpEF and HFrEF were associated with prolonged length of stay (LOS) > 1 day (aOR 1.41, 95% CI 1.31-1.53 and aOR 1.66, 95% CI 1.53-1.80) and increased hospitalization costs > median cost 24 752$ (aOR 1.26, 95% CI 1.19-1.34 and aOR 1.21, 95% CI 1.13-1.29). CONCLUSION: The prevalence of HF in AF patients undergoing percutaneous LAAO was approximately 26%. HF was not independently associated with major complications and in-patient mortality but was associated with prolonged LOS and higher hospitalization costs.

Contemporary procedural trends of Watchman percutaneous left atrial appendage occlusion in the United States.

OBJECTIVE: To determine trends in real-world utilization and in-hospital adverse events from Watchman implantation since its approval by the Food and Drug Administration in 2015. BACKGROUND: The risk of embolic stroke caused by atrial fibrillation is reduced by oral anticoagulants, but not all patients can tolerate long-term anticoagulation. Left atrial appendage occlusion with the Watchman device has emerged as an alternative therapy. METHODS: This was a retrospective cohort study utilizing data from National Inpatient Sample for calendar years 2015-2017. The outcomes assessed in this study were associated complications, in-hospital mortality, and resource utilization trends after Watchman implantation. Trends analysis were performed using analysis of variance. Multivariable adjusted logistic regression analysis was performed to determine predictors of mortality. RESULTS: A total of 17 700 patients underwent Watchman implantation during the study period. There was a significantly increased trend in the number of Watchman procedures performed over the study years (from 1195 in 2015 to 11 165 devices in 2017, p < .01). A significant decline in the rate of complications (from 26.4% in 2015% to 7.9% in 2017, p < .01) and inpatient mortality (from 1.3% in 2015% to 0.1% in 2017, p < .01) were noted. Predictors of in-hospital mortality included a higher CHA2 DS2 -VASc score (odds ratio [OR]: 2.61 per 1-point increase, 95% confidence interval [CI]: 1.91-3.57), chronic blood loss anemia (OR: 3.63, 95% CI: 1.37-9.61) and coagulopathy (OR: 4.90, 95% CI: 2.32-10.35). CONCLUSION: In contemporary United States clinical practice, Watchman utilization has increased significantly since approval in 2015, while complications and in-patient mortality have declined.

Outcomes and predictors of readmission after implantation of a percutaneous left atrial appendage occlusion device in the United States: A propensity score-matched analysis from The National Readmission Database.

BACKGROUND: Left atrial appendage occlusion (LAAO) devices have become a favorable alternative option among nonvalvular atrial fibrillation (AF) patients with long-term contraindication to anticoagulation. Real-world experience with postprocedural readmission rates and predictors of readmission in LAAO patients is limited. OBJECTIVE: To assess all-cause 30-day readmission rate and predictors of readmission after LAAO procedure in the United States. METHOD: This retrospective observational study included all AF patients undergoing percutaneous LAAO procedures in the United States from January 1, 2016, and December 31, 2017, in the National Readmission Database. The primary outcome measure was all-cause 30-day readmission. A propensity score-matched analysis compared outcomes with a non-LAAO AF cohort. RESULT: Among 14 024 LAAO procedures (age: 76 ± 8 years; 60.5% males), 9.4% were readmitted within 30-days and, 0.2% died during their index hospitalization. The most frequent primary diagnosis during readmission among LAAO was gastrointestinal bleeding (12%). The incidence of LAAO procedures increased by 102%. In the multivariate model, gender and CHA2 DS2 -VASc failed to predict readmission. Age 55-64 years had lower odds (adjusted odds ratios [aOR]: 0.41; 95% confidence interval [CI]: 0.18-0.94), while drug abuse (aOR: 4.1; 95% CI: 1.34-12.54), and deficiency anemia (aOR: 1.88; 95% CI: 1.12-3.18) had higher odds of readmission. In propensity-matched cohort, compared to non-LAAO AF, LAAO patients had lower 30-day readmission (9.4% vs. 10.98%, p = .002) and all-cause in-hospital mortality (0.19% vs. 0.57%, p < .001). CONCLUSION: The readmission rate following the LAAO procedure is substantial (approximately 10%), and largely attributable to gastrointestinal bleeding. Factors such as drug abuse and anemia must be explored further to minimize readmission risk.

Inducible and multiplex gene regulation using CRISPR-Cpf1-based transcription factors.

Targeted and inducible regulation of mammalian gene expression is a broadly important capability. We engineered drug-inducible catalytically inactive Cpf1 nuclease fused to transcriptional activation domains to tune the expression of endogenous genes in human cells. Leveraging the multiplex capability of the Cpf1 platform, we demonstrate both synergistic and combinatorial gene expression in human cells. Our work should enable the development of multiplex gene perturbation library screens for understanding complex cellular phenotypes.

BrainImageR: spatiotemporal gene set analysis referencing the human brain.

Motivation: Neuronal analyses such as transcriptomics, epigenetics and genome-wide association studies must be assessed in the context of the human brain to generate biologically meaningful inferences. It is often difficult to access primary human brain tissue; therefore, approximations are made using alternative sources such as peripheral tissues or in vitro-derived neurons. Gene sets from these studies are then assessed for their association with the post-mortem human brain. However, most analyses of post-mortem datasets are achieved by building new computational tools each time in-house, which can cause discrepancies from study to study. The field is in need of a user-friendly tool to examine spatiotemporal expression with respect to the postmortem brain. Such a tool will be of use in the molecular interrogation of neurological and psychiatric disorders, with direct advantages for the disease-modeling and human genetics communities. Results: We have developed brainImageR, an R package that calculates both the spatial and temporal association of a dataset with post-mortem human brain. BrainImageR identifies anatomical regions enriched for candidate gene set expression. It further predicts the developmental time point of the sample, a task that has become increasingly important in the field of in vitro neuronal modeling. These functionalities of brainImageR enable a quick and efficient characterization of a given dataset across normal human brain development. Availability and implementation: BrainImageR is released under the Creative Commons CC BY-SA 4.0 license and can be accessed directly at brainimager.salk.edu or the R code can be downloaded through github at https://github.com/saralinker/brainImageR.

Atrial fibrillation in patients with heart failure with preserved ejection fraction.

PURPOSE OF REVIEW: To review the shared pathology of atrial fibrillation and heart failure with preserved ejection fraction (HFpEF) and the prognostic, diagnostic, and treatment challenges incurred by the co-occurrence of these increasingly prevalent diseases. RECENT FINDINGS: Multiple risk factors and mechanisms have been proposed as potentially linking atrial fibrillation and HFpEF, with systemic inflammation more recently being invoked. Nonvitamin K oral anticoagulants, left atrial appendage occlusion devices, and catheter ablation have emerged as alternative treatment options. Other novel pharmacological agents, such as neprilysin inhibitors, need to be studied further in this patient population. SUMMARY: Atrial fibrillation and HFpEF commonly co-occur because of their shared risk factors and pathophysiology and incur increased morbidity and mortality relative to either condition alone. Although the presence of both diseases can often make each diagnosis difficult, it is important to do so early in the disease course as there are now a variety of treatment options aimed at improving symptoms and quality of life, slowing disease progression, and improving prognosis. However, more research needs to be performed on the role of catheter ablation in this population. Novel pharmacologic and procedural treatment options appear promising and may further improve the treatment options available to this growing population.

Clinical factors associated with baseline history of atrial fibrillation and subsequent clinical outcomes following initial implantable cardioverter-defibrillator placement.

BACKGROUND: Atrial fibrillation (AF) is frequently present in patients with heart failure (HF) and an implantable cardioverter-defibrillator (ICD). This study aims to identify clinical factors associated with a baseline history of AF in ICD recipients, and compares subsequent clinical outcomes in those with and without a baseline history of AF. METHODS: We studied 566 consecutive first-time ICD recipients at an academic center between 2011 and 2018. Logistic regression multivariable analyses were used to identify clinical factors associated with a baseline history of AF at the time of ICD implant. Cox-proportional hazard regression models were constructed for multivariate analysis to examine associations between a baseline history of AF with subsequent clinical outcomes, including ICD therapies, HF readmission, and all-cause mortality. RESULTS: Of all patients, 201 (36%) had a baseline history of AF at the time of ICD implant. In multivariate analyses, clinical factors associated with a baseline history of AF included hypertension, valvular heart disease, body weight, PR interval, and serum creatinine level. After multivariate adjustment for potential confounders, a baseline history of AF was associated with an increased risk of anti-tachycardia pacing (HR = 1.84, 95% CI = 1.19-2.85, P = .006), appropriate ICD shocks (HR = 1.80, 95% CI = 1.05-3.09, P = .032), and inappropriate ICD shocks (HR = 3.72, 95% CI = 1.7-7.77, P = .0001), but not other adverse outcomes. CONCLUSION: Among first-time ICD recipients, specific clinical characteristics were associated with a baseline history of AF at the time of ICD implant. After adjustment for potential confounders, a baseline history of AF was associated with a higher risk of all ICD therapies in follow-up.

Subventricular zone neural precursor cell responses after traumatic brain injury and binge alcohol in male rats.

Traumatic brain injury (TBI) is a major cause of disability worldwide. Additionally, many TBI patients are intoxicated with alcohol at the time of injury, but the impact of acute intoxication on recovery from brain injury is not well understood. We have previously found that binge alcohol prior to TBI impairs spontaneous functional sensorimotor recovery. However, whether alcohol administration in this setting affects reactive neurogenesis after TBI is not known. This study, therefore, sought to determine the short- and long-term effects of pre-TBI binge alcohol on neural precursor cell responses in the subventricular zone (SVZ) following brain injury in male rats. We found that TBI alone significantly increased proliferation in the SVZ as early as 24 hr after injury. Surprisingly, binge alcohol alone also significantly increased proliferation in the SVZ after 24 hr. However, a combined binge alcohol and TBI regimen resulted in decreased TBI-induced proliferation in the SVZ at 24 hr and 1 week post-TBI. Furthermore, at 6 weeks after TBI, binge alcohol administered at the time of TBI significantly decreased the TBI-induced neuroblast response in the SVZ and the rostral migratory stream (RMS). The results from this study suggest that pre-TBI binge alcohol negatively impacts reparative processes in the brain by decreasing short-term neural precursor cell proliferative responses as well as long-term neuroblasts in the SVZ and RMS.

Association of insurance type with receipt of oral anticoagulation in insured patients with atrial fibrillation: A report from the American College of Cardiology NCDR PINNACLE registry.

BACKGROUND: It is poorly understood whether insurance type may be a major contributor to the underuse of oral anticoagulation (OAC) among patients with atrial fibrillation (AF), particularly for novel oral anticoagulants (NOACs). METHODS: We performed a retrospective cohort registry study of patients with insurance, AF, CHA2DS2-VASc ≥2, and at least one outpatient encounter recorded in the ACC NCDR's PINNACLE Registry between January 1, 2011 and December 31, 2014. We used hierarchical regression, adjusting for patient characteristics and clustering by physician, to evaluate the association of insurance type (Private, Military, Medicare, Medicaid, Other) with receipt of OAC (any OAC, warfarin, or NOAC). RESULTS: In 363,309 patients (age 75±10; 48% female), we found a significant difference in proportions of OAC and NOAC prescription across insurance types (OAC: Military 53%, Private 53%, Medicare 52%, Other 41%, Medicaid 41%, P<.001; NOAC: Military 24%, Private 19%, Medicare 17%, Other 17%, Medicaid 8%, P<.001). After adjustment for patient characteristics and facility, private, Medicaid, and other insurance were independently associated with a lower odds of OAC prescription relative to Medicare, but military insured patients were not significantly different. After adjustment, military and private insurance were independently associated with a higher odds of NOAC prescription relative to Medicare, while Medicaid and other insurance were associated with a lower odds of NOAC prescription. CONCLUSIONS: In a contemporary US AF population, there was significant variation of OAC prescription across insurance plans, with the highest among private and Medicare insured patients. These differences may indicate that insurance plan, and its associated pharmacy benefits, affect the pace of diffusion of new therapies.