Trends in mortality risk of patients with congenital heart disease during the COVID-19 pandemic.

BACKGROUND: Cardiovascular conditions are considered risk factors for poor outcomes associated with COVID-19. However, the effect of the COVID-19 pandemic on the mortality of patients with congenital heart disease (CHD) is unclear. Our study aims to examine the trends in mortality risk of CHD patients during the COVID-19 pandemic. METHODS: This is a retrospective cohort study from the Pediatric Cardiac Care Consortium, a US-based registry of interventions for CHD. We included patients having US residence and direct identifiers; death events were captured by matching with the National Death Index. The observation window (2017-2022) was divided into pre-COVID-19 and COVID-19 era defined around the national onset of COVID-19 disease in 2020. Stratified Cox model was used to assess all-cause mortality between the pre- and the COVID-19 era. RESULTS: Among 45,130 patients with CHD (median age in 2017: 23.3 years, IQR: 19.0-28.4), 503 deaths occurred during the pandemic with 44 deaths (8.7%) attributed to COVID-19 (COVID-19 mortality rate of 0.09%). The overall risk of death for patients with all types of CHD during the pandemic was significantly higher compared to the pre-COVID-19 era (aHR 1.28, 95%CI: 1.08-1.53), with a differential trend towards increased risk in patients with two-ventricle (aHR 1.44, 95% CI: 1.19-1.76) vs unchanged risk for those with single ventricle CHD (aHR = 0.83, 95% CI: 0.57-1.21). Adjusted subgroup analysis revealed a higher risk of death during the pandemic for CHD patients with male and chromosomal abnormalities. The excess deaths during the pandemic were attributed to COVID-19 itself rather than CHD or cardiovascular conditions. CONCLUSION: In this large CHD cohort study, there was a higher risk of death among CHD patients with male and chromosomal abnormalities. A differential trend towards higher risk for those with two vs. unchanged risk for single ventricle CHD was presented. The excess mortality was attributed to the COVID-19 itself and not to conditions potentially related to deferral of care. These results justify targeted protective measures towards the CHD population and may provide guidance for public health and medical care response in future epidemics.

Sex differences in treatment strategy and adverse outcomes among patients 75 and older with atrial fibrillation in the MarketScan database.

BACKGROUND: Women with atrial fibrillation (AF) experience greater symptomatology, worse quality of life, and have a higher risk of stroke as compared to men, but are less likely to receive rhythm control treatment. Whether these differences exist in elderly patients with AF, and whether sex modifies the effectiveness of rhythm versus rate control therapy has not been assessed. METHODS: We studied 135,850 men and 139,767 women aged ≥ 75 years diagnosed with AF in the MarketScan Medicare database between 2007 and 2015. Anticoagulant use was defined as use of warfarin or a direct oral anticoagulant. Rate control was defined as use of rate control medication or atrioventricular node ablation. Rhythm control was defined by use of anti-arrhythmic medication, catheter ablation or cardioversion. We used multivariable Poisson and Cox regression models to estimate the association of sex with treatment strategy and to determine whether the association of treatment strategy with adverse outcomes (bleeding, heart failure and stroke) differed by sex. RESULTS: At the time of AF, women were on average (SD) 83.8 (5.6) years old and men 82.5 (5.2) years, respectively. Compared to men, women were less likely to receive an anticoagulant or rhythm control treatment. Rhythm control (vs. rate) was associated with a greater risk for heart failure with a significantly stronger association in women (HR women = 1.41, 95% CI 1.34-1.49; HR men = 1.21, 95% CI 1.15-1.28, p < 0.0001 for interaction). No sex differences were observed for the association of treatment strategy with the risk of bleeding or stroke. CONCLUSION: Sex differences exist in the treatment of AF among patients aged 75 years and older. Women are less likely to receive an anticoagulant and rhythm control treatment. Women were also at a greater risk of experiencing heart failure as compared to men, when treated with rhythm control strategies for AF. Efforts are needed to enhance use AF therapies among women. Future studies will need to delve into the mechanisms underlying these differences.

Thirty-Year Survival after Cardiac Surgery for Patients with Turner Syndrome.

OBJECTIVE: To evaluate long-term survival in patients with Turner syndrome after congenital heart surgery with a focus on left heart obstructive lesions (LHOLs). STUDY DESIGN: We queried the Pediatric Cardiac Care Consortium, a US-based registry of congenital heart surgery, for patients with Turner syndrome undergoing congenital heart surgery at <21 years of age between 1982 and 2011. Outcomes were obtained from the Pediatric Cardiac Care Consortium and from national death and transplant registries through 2019. Survival of patients with Turner syndrome and nonsyndromic patients with similar LHOL was compared by Kaplan-Meier survival curves and Cox regression adjusted for age, congenital heart disease, and era. RESULTS: We identified 179 patients with Turner syndrome operated for LHOL: 161 with 2-ventricle lesions (coarctation n = 149, aortic stenosis n = 12) and 18 with hypoplastic left heart (HLH) variants. There were 157 with 2-ventricle LHOL and 6 with HLH survived to discharge. Among survivors to hospital discharge, the 30-year transplant-free survival was 90.4% for Turner syndrome with 2-ventricle lesions and 90.9% for nonsyndromic comparators (adjusted hazard ratio [aHR] 1.15, 95% CI 0.64-2.04). The postdischarge survival for HLH was 33% for Turner syndrome and 51% for nonsyndromic patients, with these numbers being too small for meaningful comparisons. There was a higher risk for cardiovascular disease events in patients with Turner syndrome vs male (aHR 3.72, 95% CI 1.64-8.39) and female comparators (aHR 4.55, 95% CI 1.87-11.06) excluding heart failure deaths. CONCLUSIONS: The 30-year transplant-free survival is similar for patients with Turner syndrome and nonsyndromic comparators with operated 2-ventricle LHOL without excess congenital heart disease risk. However, patients with Turner Syndrome still face increased cardiovascular disease morbidity, stressing the importance of lifelong comorbidity surveillance in this population.

Association of Type of Antidepressant Initiation with Bleeding Risk in Atrial Fibrillation Patients Taking Oral Anticoagulants.

BACKGROUND: Inconsistent evidence suggests that use of certain antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs), in patients using oral anticoagulants (OACs) might be associated with an elevated risk of bleeding. OBJECTIVE: This study aims to investigate the risk of bleeding associated with initiation of different types of antidepressants among atrial fibrillation (AF) patients on OAC therapy. PATIENTS AND METHODS: A total of 30,336 AF patients (mean age 72.2 years; 54% female) on OAC therapy that started antidepressant treatment were identified from the Truven Health Analytics MarketScan Commercial and Medicare Databases for the period 2007-2015. Exposure was defined as filling a prescription for antidepressant, and categorized as SSRI, serotonin/norepinephrine reuptake inhibitors (SNRIs), serotonin reuptake inhibitors (SRIs), tricyclic antidepressants (TCAs), or other antidepressants. The primary outcome was incident hospitalized bleeding. Associations of antidepressant type with bleeding were assessed calculating hazard ratios (HRs) and 95% confidence intervals (CIs) with adjusted Cox models in pairwise propensity score-matched cohorts. RESULTS: During a mean follow-up of 21 months, we identified 1612 bleeding episodes. In pairwise comparisons, SSRI use was associated with an increased risk of bleeding when compared to most other antidepressants (HR 1.22, 95% CI 0.96-1.54 vs SNRI; HR 1.10, 95% CI 0.90-1.35 vs SRI; HR 1.03, 95% CI 0.82-1.30 vs TCA). SNRI use was associated with the lowest bleeding risk. Results did not differ by OAC type, age, and sex. CONCLUSIONS: Among AF patients on OAC initiating antidepressants, risk of bleeding varied across antidepressant type. This information can inform treatment choices among patients receiving OAC.

Associations of anger, vital exhaustion, anti-depressant use, and poor social ties with incident atrial fibrillation: The Atherosclerosis Risk in Communities Study.

BACKGROUND: We examined the relationships of anger, vital exhaustion, anti-depressant use, and poor social ties with incident atrial fibrillation in a biracial cohort of middle and older-aged adults. METHODS: This analysis included 11,445 Atherosclerosis Risk in Communities Study participants who were free of atrial fibrillation at baseline in 1990-1992. Vital exhaustion was assessed at baseline and defined as a score in the highest quartile on the 21-item Vital Exhaustion Questionnaire. Baseline anti-depressant use was self-reported. The Spielberger Trait Anger Scale to assess anger and both the Interpersonal Support Evaluation List and the Lubben Social Network Scale to assess social ties were also administered at baseline. The primary outcome was incident atrial fibrillation throughout 2016, identified by electrocardiogram, hospital discharge coding of atrial fibrillation, and death certificates. RESULTS: A total of 2220 incident atrial fibrillation cases were detected over a median follow-up of 23.4 years. After adjusting for age, race-center, sex, education, and height, participants in the 4th Vital Exhaustion Questionnaire quartile (referent = 1st Vital Exhaustion Questionnaire quartile) and those reporting anti-depressant use were at increased risk for atrial fibrillation (hazard ratio = 1.45, 95% confidence interval 1.29-1.64 for Vital Exhaustion Questionnaire; hazard ratio = 1.37, 95% confidence interval 1.11-1.69 for anti-depressant use). The increased atrial fibrillation risk observed for 4th Vital Exhaustion Questionnaire quartile participants remained significant after additional adjustment for relevant comorbidities (hazard ratio = 1.20; confidence interval 1.06-1.35). No significant associations were observed for anger or poor social ties with development of atrial fibrillation. CONCLUSIONS: Vital exhaustion is associated with an increased risk of incident atrial fibrillation.

Association of arterial stiffness with incident atrial fibrillation: a cohort study.

BACKGROUND: Stiff arteries increase left ventricular (LV) end-systolic workload, leading over time to left atrial and ventricular remodeling, and providing the substrate for atrial fibrillation (AF) development. We investigated if carotid femoral pulse wave velocity (cfPWV), a measure of central arterial stiffness, is associated with incident AF. METHODS: In 2011-2013, cfPWV was measured in 3882 participants of the Atherosclerosis Risk in Communities Cohort Study (ARIC) without prevalent AF. Participants were followed through 2017 for the incidence of AF. Individuals were categorized in cfPWV quartiles based on visit measurements. Multivariable Cox regression models were used to evaluate the association of cfPWV with incident AF. RESULTS: Mean age was 75 years (SD 5), 60% were female and 20% were African American. Over a median follow-up of 5.5 years we identified 331 incident cases of AF. cfPWV demonstrated U-shaped associations with AF risk. In models adjusted for age, race, center, sex, education levels, and hemodynamic and clinical factors, hazard ratios (HR) of AF for participants in the first, third and fourth quartiles were 1.49 (95% CI 1.06, 2.10), 1.59 (1.14, 2.10), and 1.56(1.10, 2.19), respectively, compared to those in the second quartile. CONCLUSION: Among community-dwelling older adults, low and high central arterial stiffness is associated with AF risk.

Impact of oral anticoagulation choice on healthcare utilization for the primary treatment of venous thromboembolism.

Little is known about the impact of oral anticoagulation (OAC) choice on healthcare encounters during venous thromboembolism (VTE) primary treatment. Among anticoagulant-naïve patients with VTE, we tested the hypotheses that healthcare utilization would be lower among users of direct OACs (DOACs; rivaroxaban or apixaban) than among users of warfarin. MarketScan databases for years 2016 and 2017 were used; healthcare utilization was identified in the first 6 months after initial VTE diagnoses. The 23,864 patients with VTE had on average 0.2 ± 0.5 hospitalizations, spent 1.3 ± 5.2 days in the hospital, had 5.7 ± 5.1 outpatient encounters, and visited an emergency department 0.4 ± 1.1 times. As compared to warfarin, rivaroxaban and apixaban were associated with fewer hospitalizations, days hospitalized, outpatient office visits, and emergency department visits after accounting for age, sex, comorbidities, and medications. Hospitalization rates were 24% lower (incidence rate ratio (IRR): 0.76; 95% CI: 0.69, 0.83) with rivaroxaban and 22% lower (IRR: 0.78; 95% CI: 0.71, 0.87) with apixaban, as compared to warfarin (IRR: 1.00 (reference)). Healthcare utilization was similar between apixaban and rivaroxaban users. Patients with VTE prescribed rivaroxaban and apixaban had lower healthcare utilization than those prescribed warfarin, while there was no difference when comparing apixaban to rivaroxaban. These findings complement existing literature supporting the use of DOACs over warfarin.

Polypharmacy, Adverse Outcomes, and Treatment Effectiveness in Patients ≥75 With Atrial Fibrillation.

Background Polypharmacy is highly prevalent in elderly people with chronic conditions, including atrial fibrillation (AF). The impact of polypharmacy on adverse outcomes and on treatment effectiveness in elderly patients with AF remains unaddressed. Methods and Results We studied 338 810 AF patients ≥75 years of age enrolled in the MarketScan Medicare Supplemental database in 2007-2015. Polypharmacy was defined as ≥5 active prescriptions at AF diagnosis (defined by the presence of International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] codes) based on outpatient pharmacy claims. AF treatments (oral anticoagulation, rhythm and rate control) and cardiovascular end points (ischemic stroke, bleeding, heart failure) were defined based on inpatient, outpatient, and pharmacy claims. Multivariable Cox models were used to estimate associations of polypharmacy with cardiovascular end points and the interaction between polypharmacy and AF treatments in relation to cardiovascular end points. Prevalence of polypharmacy was 52%. Patients with polypharmacy had increased risk of major bleeding (hazard ratio [HR], 1.16; 95% CI, 1.12-1.20) and heart failure (HR, 1.33; 95% CI, 1.29-1.36) but not ischemic stroke (HR, 0.96; 95% CI, 0.92-1.00), compared with those not receiving polypharmacy. Polypharmacy status did not consistently modify the effectiveness of oral anticoagulants. Rhythm control (versus rate control) was more effective in preventing heart failure hospitalization in patients not receiving polypharmacy (HR, 0.87; 95% CI, 0.76-0.99) than among those with polypharmacy (HR, 0.98; 95% CI, 0.91-1.07; P=0.02 for interaction). Conclusion Polypharmacy is common among patients ≥75 with AF, is associated with adverse outcomes, and may modify the effectiveness of AF treatments. Optimizing management of polypharmacy in AF patients ≥75 may lead to improved outcomes.

Association of Multimorbidity with Cardiovascular Endpoints and Treatment Effectiveness in Patients 75 Years and Older with Atrial Fibrillation.

BACKGROUND: The burden imposed by multimorbidity on outcomes and on the effectiveness of atrial fibrillation therapies in elderly adults with atrial fibrillation is unknown. METHODS: Patients with nonvalvular atrial fibrillation ages ≥75 years in the MarketScan Medicare Supplemental database from 2007-2015. Prevalence of 14 chronic conditions at the time of atrial fibrillation diagnosis were obtained and classified as cardiometabolic or noncardiometabolic. Cox regression estimated the associations of the number and type of conditions with stroke, severe bleeding, and heart failure hospitalizations. Tests for interaction were assessed between atrial fibrillation treatments and multimorbidity. RESULTS: Among 275,617 patients with atrial fibrillation (mean age 83 years, 51% women), the mean (SD) number of conditions per participant was 3.0 (2.1). Over a mean follow-up of 23 months, 7814 strokes, 13,622 severe bleeds, and 19,252 heart failure events occurred. After adjustment, an increase in the number of cardiometabolic conditions was associated with greater risk of stroke (hazard ratio [HR] 1.07; 95% confidence interval [CI], 1.05-1.10), severe bleeding (HR 1.09; 95% CI, 1.07-1.11), and heart failure (HR 1.19, 95% CI, 1.18-1.20). In contrast, number of noncardiometabolic conditions had weak or null associations with risk of cardiovascular endpoints. Overall, the effectiveness of atrial fibrillation treatment on stroke and heart failure were similar across multimorbidity status, but bleeding risk associated with atrial fibrillation treatments was higher in patients with overall and subgroup multimorbidity. CONCLUSION: Cardiometabolic multimorbidity was associated with worse outcomes and modified bleeding risk in atrial fibrillation patients. These findings underscore the impact of cardiometabolic conditions on atrial fibrillation outcomes and highlights the need to incorporate multimorbidity management in atrial fibrillation treatment guidelines.

Association and impact of hypertension defined using the 2017 AHA/ACC guidelines on the risk of atrial fibrillation in The Atherosclerosis Risk in Communities study.

BACKGROUND: Hypertension is an established risk factor for the development of atrial fibrillation (AF). We evaluated the association and population impact of hypertension, defined using the new 2017 guidelines, on risk of AF. METHODS: In this analysis, we included 14,915 participants in the Atherosclerosis Risk in Communities study without history of AF. Participants underwent blood pressure measurements at baseline and their antihypertensive medication use was assessed. Incident AF was ascertained from study electrocardiograms, hospital records and death certificates. Cox proportional models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) of AF among individuals with hypertension based on the JNC7 and 2017 ACC/AHA guidelines. Poisson models were used to obtain risk ratios and calculate population-attributable fractions (PAFs). RESULTS: We identified 2891 cases of incident AF during 21.4 years of mean follow-up. Prevalence of hypertension was 34 and 48% under the JNC7 and 2017 ACC/AHA definitions, respectively. HRs (95%CI) of AF in hypertensives versus non-hypertensives were 1.44 (1.32, 1.56) and 1.37 (1.26, 1.48) after multivariable adjustment under the old and new guidelines, respectively. The corresponding PAF (95%CI) using the old and new guidelines were 11% (8, 13%) and 13% (9, 16%), respectively. CONCLUSIONS: Overall, our analysis shows that even though the prevalence of hypertension using the new criteria is 40% higher than with the old criteria, this does not translate into meaningful increases in AF attributable to hypertension. These results suggest that prevention or treatment of hypertension based on the new (versus old) guidelines may have limited impact on AF incidence.

Sex and racial differences in cardiovascular disease risk in patients with atrial fibrillation.

BACKGROUND: Outcomes among atrial fibrillation (AF) patients may differ according to race/ethnicity and sex due to differences in biology, the prevalence of cardiovascular risk factors, and the use and effectiveness of AF treatments. We aimed to characterize patterns of cardiovascular risk across subgroups of AF patients by sex and race/ethnicity, since doing so may provide opportunities to identify interventions. We also evaluated whether these patterns changed over time. METHODS: We utilized administrative claims data from the Optum Clinformatics® Datamart database from 2009 to 2015. Patients with AF with ≥6 months of enrollment prior to the first non-valvular AF diagnosis were included in the analysis. Final analysis utilized Cox proportional hazard models to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for cardiovascular outcomes stratified by sex and race/ethnicity. An additional analysis stratified outcomes by calendar year of AF diagnosis to evaluate changes in outcomes over time. RESULTS: In a cohort of 380,636 AF patients, women had a higher risk of ischemic stroke [HR (95% CI): 1.25 (1.19, 1.31)] and lower risk of heart failure and myocardial infarction [HR (95% CI): 0.91 (0.88, 0.94) and 0.81 (0.77, 0.86), respectively)] compared to men. Black patients had elevated risk across all endpoints compared to whites, while Hispanics and Asian Americans showed no significant differences in any outcome compared to white patients. These sex and race/ethnic differences did not change over time. CONCLUSIONS: We found sex and race/ethnic differences in risk of cardiovascular outcomes among AF patients, without evidence of improvement over time.

A new model to predict ischemic stroke in patients with atrial fibrillation using warfarin or direct oral anticoagulants.

BACKGROUND: Stroke risk stratification scores (eg, CHA2DS2-VASc) are used to tailor therapeutic recommendations for patients with atrial fibrillation (AF) in different risk groups. OBJECTIVE: The purpose of this study was to develop a tool to estimate stroke risk in patients receiving oral anticoagulants (OACs) and to identify patients who remain at high risk for stroke despite anticoagulation therapy. METHODS: Patients with nonvalvular AF initiating OACs were identified in the MarketScan data from 2007 to 2015. Using bootstrapping methods and backward selection of 44 candidate variables, we developed a model that selected variables predicting stroke. The final model was validated in patients with nonvalvular AF in the Optum database in the period 2009-2015. In both databases, the discrimination of existing stroke scores were individually evaluated and compared with our new model termed the AntiCoagulaTion-specific Stroke (ACTS) score. RESULTS: Among 135,523 patients with AF initiating OACs in the MarketScan dataset, 2028 experienced an ischemic stroke after anticoagulant initiation. The stepwise model identified 11 variables (including type of OAC) associated with ischemic stroke. The discrimination (C statistic) of the model was adequate (0.68; 95% confidence interval [CI] 0.66-0.70), showing excellent calibration (χ2 = 6.1; P = .73). ACTS was then applied to 84,549 AF patients in the Optum dataset (1408 stroke events) and showed similar discrimination (C statistic 0.67; 95% CI 65-0.69). However, previously developed predictive models had similar discriminative ability (CHA2DS2-VASc 0.67; 95% CI 0.65-0.68). CONCLUSION: A novel model to identify AF patients at higher risk of ischemic stroke, using extensive administrative health care data including type of anticoagulant, did not perform better than established simpler models.

Geographic Disparities in the Incidence of Stroke among Patients with Atrial Fibrillation in the United States.

AIM: To determine whether regional variation in stroke incidence exists among individuals with AF. METHODS: Using healthcare utilization claims from 2 large US databases, MarketScan (2007-2014) and Optum Clinformatics (2009-2015), and the 2010 US population as the standard, we estimated age-, sex-, race- (only in Optum) standardized stroke incidence rates by the 9 US census divisions. We also used Poisson regression to examine incidence rate ratios (IRR) of stroke and the probability of anticoagulation prescription fills across divisions. RESULTS: Both databases combined included 970,683 patients with AF who experienced 15,543 strokes, with a mean follow-up of 23 months. In MarketScan, the age- and sex-standardized stroke incidence rate was highest in the Middle Atlantic and East South Central divisions at 3.8/1000 person-years (PY) and lowest in the West North Central at 3.2/1000 PY. The IRR of stroke and the probability of anticoagulation fills were similar across divisions. In Optum Clinformatics, the age-, sex-, and race-standardized stroke incidence rate was highest in the East North Central division at 5.0/1000 PY and lowest in the New England division at 3.3/1000 PY. IRR of stroke and the probability of anticoagulation fills differed across divisions when compared to New England. CONCLUSIONS: These findings suggest regional differences in stroke incidence among AF patients follow a pattern that differs from the hypothesized trend found in the general population and that other factors may be responsible for this new pattern. Cross-database differences provide a cautionary tale for the identification of regional variation using health claims data.

Association of Oral Anticoagulant Type With Risk of Dementia Among Patients With Nonvalvular Atrial Fibrillation.

Background Oral anticoagulants ( OACs ) in patients with atrial fibrillation ( AF ), in addition to reducing stroke risk, could also prevent adverse cognitive outcomes. The purpose of this study was to compare the risk of dementia incidence across patients with AF initiating different OAC s. Methods and Results We identified patients with nonvalvular AF initiating OAC s in 2 US healthcare claim databases, MarketScan (2007-2015) and Optum Clinformatics (2009-2015). Dementia, comorbidities, and use of medications were defined on the basis of inpatient and outpatient claims. We performed head-to-head comparisons of warfarin, dabigatran, rivaroxaban, and apixaban in propensity score-matched cohorts. We calculated hazard ratios ( HR s) and 95% confidence intervals ( CI s) of incident dementia for each propensity score-matched cohort and meta-analyzed database-specific results. We analyzed 307 099 patients with AF from the MarketScan database and 161 346 from the Optum database, of which 6572 and 4391, respectively, had a diagnosis of incident dementia. The mean follow-up of each cohort ranged between 0.7 and 2.2 years. Patients initiating direct OACs experienced lower rates of dementia than those initiating warfarin (dabigatran: HR , 0.85; 95% CI , 0.71-1.01; rivaroxaban: HR , 0.85; 95% CI , 0.76-0.94; apixaban: HR , 0.80; 95% CI , 0.65-0.97). There were no differences in rates of dementia comparing direct OAC user groups (dabigatran versus rivaroxaban: HR , 1.02; 95% CI , 0.79-1.32; dabigatran versus apixaban: HR , 0.92; 95% CI , 0.63-1.36; apixaban versus rivaroxaban: HR , 1.01; 95% CI , 0.86-1.19). Conclusions Patients with AF initiating direct OACs experienced lower rates of incident dementia than warfarin users. No obvious benefit was observed for any particular direct OAC in relation to dementia rates.

Provider Specialty, Anticoagulation, and Stroke Risk in Patients With Atrial Fibrillation and Cancer.

BACKGROUND: It is unknown whether early cardiology involvement shortly after atrial fibrillation (AF) diagnosis is associated with favorable outcomes in AF patients who have cancer. OBJECTIVES: The purpose of this study was to examine the relationship between early cardiology involvement after AF diagnosis in patients with history of cancer. METHODS: This study examined associations of early cardiology involvement with oral anticoagulation use, stroke, and bleeding among nonvalvular AF patients (n = 388,045; mean age 68 ± 15 years; 59% male) with a history of cancer (past or active) from the MarketScan database (2009 to 2014). International Classification of Disease-9th Revision-Clinical Modification codes in any position were used to identify cancer diagnosis prior to AF diagnosis. Provider specialty and filled anticoagulant prescriptions 3 months prior to and 6 months after AF diagnosis were obtained. Poisson regression models were used to compute the probability of an oral anticoagulant prescription fill, and Cox regression was used to estimate the risks of stroke and major bleeding. RESULTS: A total of 64,016 (17%) AF patients had a history of cancer. Cardiology involvement was less likely to occur among patients with a history of cancer than those without (relative risk [RR]: 0.92 [95% confidence interval (CI): 0.91 to 0.93]). Patients with history of cancer were less likely to fill prescriptions for anticoagulants (RR: 0.89 [95% CI: 0.88 to 0.90]) than those without cancer, and similar results were observed across cancer types. Patients with cancer were more likely to fill prescriptions for anticoagulants (RR: 1.48 [95% CI: 1.45 to 1.52]) if seen by a cardiologist. A reduced risk of stroke (hazard ratio: 0.89 [95% CI: 0.81 to 0.99]) was observed among all cancer patients who were seen by a cardiology provider, without an increased risk of bleeding (hazard ratio: 1.04 [95% CI: 0.95 to 1.13]). Similar results were observed when the analysis was stratified by active versus remote history of cancer. CONCLUSIONS: Although AF patients with cancer were less likely to see a cardiologist, or fill anticoagulant prescriptions, cardiology involvement was associated with increased anticoagulant prescription fills and favorable AF-related outcomes in AF patients with cancer.

A new model to predict major bleeding in patients with atrial fibrillation using warfarin or direct oral anticoagulants.

BACKGROUND: No scores presently exist to predict bleeding in atrial fibrillation (AF) populations using direct oral anticoagulants (DOACs). We used data from two independent healthcare claims databases to develop and validate a predictive model of major bleeding in a contemporary AF population. METHODS: Patients with non-valvular AF initiating oral anticoagulation were identified in the MarketScan databases from 2007-2014. Using Cox regression models in 1000 bootstrapped samples, we developed a model that selected variables predicting major bleeding in the first year after anticoagulant initiation. The final model was validated in patients with non-valvular AF in the Optum Clinformatics database in the period 2009-2015. The discriminative ability of existing bleeding scores were individually evaluated and compared with the new bleeding model termed Anticoagulation-specific Bleeding Score (ABS) in both MarketScan and Optum. RESULTS: Among 119,083 patients with AF initiating oral anticoagulation in the derivation cohort, 4,030 experienced a bleeding event. The variable selection model identified 15 variables (including individual type of oral anticoagulant) associated with major bleeding. Discrimination of the model was modest [c-statistic 0.68, 95% confidence interval (CI) 0.67-0.69]. The model was subsequently applied to 81,285 AF patients in the validation data set (3,238 bleeding events), showing similar discrimination (c-statistic 0.68, 95% CI 0.67-0.69). In both cohorts, the predictive performance of the ABS was better than the existing models for bleeding prediction in AF. CONCLUSIONS: We developed a model that uses administrative healthcare data for the identification of AF patients at higher risk of bleeding after initiation of oral anticoagulation, taking into account the lower bleeding risk in DOAC compared to warfarin users.

Influence of Sociodemographic Factors and Provider Specialty on Anticoagulation Prescription Fill Patterns and Outcomes in Atrial Fibrillation.

Early cardiology involvement after atrial fibrillation (AF) diagnosis is associated with increased oral anticoagulant prescription fills and reduced stroke risk. It is unknown if this association varies by race, sex, or education. We examined anticoagulant fills in 223,891 patients with incident nonvalvular AF (mean age = 71 years; 44% women; 84% white; 9% black; 5% Hispanic; 2% Asian) from the Optum Clinformatics database (2009 to 2014). Provider specialty and filled anticoagulant prescriptions 3 months before and 6 months after AF diagnosis were obtained. Poisson regression was used to compute the probability of oral anticoagulant prescription fill and Cox regression was used to estimate the risk of stroke and major bleeding. Cardiology involvement was less likely among nonwhites (white = Referent; black = relative risk = 0.96, 95% confidence interval (0.95 to 0.97); Hispanic = 0.99 (0.98 to 1.00); Asian = 0.95 (0.93 to 0.97)) and women (0.92 (0.91 to 0.93)), but more likely with higher education level (high school or less = Referent; some college = 1.03 (1.02 to 1.04); college or more = 1.08 (1.07 to 1.09)). Patients seen by cardiology providers were more likely to fill anticoagulant prescriptions (Any = 1.67 (1.64 to 1.69); direct oral anticoagulants = 2.59 (2.49 to 2.68); warfarin = 1.38 (1.35 to 1.41)) compared with patients not seen by a cardiology provider. Patients seen by a cardiologist had a reduced stroke risk (hazard ratio = 0.84 (0.79 to 0.88)) and similar bleeding risk (1.01 (0.96 to 1.06)). Outcomes did not vary by race, sex, or education level. In conclusion, although race, sex, and education differences exist in early cardiology involvement after AF diagnosis, the influence of cardiology involvement on anticoagulant prescription fills and AF-related outcomes does not vary by these factors. Initiatives to improve early cardiology referral in nonwhites, women, and those with lower educational attainment may improve AF outcomes.

Provider Specialty, Anticoagulation Prescription Patterns, and Stroke Risk in Atrial Fibrillation.

BACKGROUND: Differences in anticoagulation rates and direct oral anticoagulant use by provider specialty may identify an area of practice improvement to reduce future stroke events in patients with atrial fibrillation (AF). METHODS AND RESULTS: We examined anticoagulant prescription fills in 388 045 (mean age, 68±15 years; 59% male) patients with incident AF from the MarketScan databases between 2009 and 2014. Provider specialty and filled anticoagulant prescriptions around the time of AF diagnosis (3 months before through 6 months after) were obtained from outpatient services and pharmacy claims. We estimated the association of provider specialty (cardiology versus primary care) with filling oral anticoagulant prescriptions, adjusting for patient characteristics. The risk of stroke and bleeding events also was explored. A total of 235 739 patients (61%) had a cardiology provider claim, whereas 152 306 (39%) were exclusively managed by primary care. Patients seen by cardiology providers were more likely to fill anticoagulant prescriptions than those seen by primary care (39% versus 27%; relative risk, 1.39; 95% confidence interval [CI], 1.37-1.40). Differences were observed for direct oral anticoagulants (relative risk, 1.74; 95% CI, 1.71-1.78) and warfarin (relative risk, 1.24; 95% CI, 1.22-1.26). A reduced risk of stroke events was observed among those seen by cardiology providers (hazard ratio, 0.90; 95% CI, 0.86-0.94) compared with primary care, without an increased bleeding risk (hazard ratio, 1.03; 95% CI, 0.98-1.07). CONCLUSIONS: Patients seen by an outpatient cardiology provider shortly after AF diagnosis were more likely to initiate oral anticoagulation and were at lower risk of future stroke events without a higher rate of bleeding. Early referral to cardiology specialists may increase initiation of anticoagulant therapies and improve outcomes in AF.

Systems-level analysis reveals selective regulation of Aqp2 gene expression by vasopressin.

Vasopressin-mediated regulation of renal water excretion is defective in a variety of water balance disorders in humans. It occurs in part through long-term mechanisms that regulate the abundance of the aquaporin-2 water channel in renal collecting duct cells. Here, we use deep DNA sequencing in mouse collecting duct cells to ask whether vasopressin signaling selectively increases Aqp2 gene transcription or whether it triggers a broadly targeted transcriptional network. ChIP-Seq quantification of binding sites for RNA polymerase II was combined with RNA-Seq quantification of transcript abundances to identify genes whose transcription is regulated by vasopressin. (View curated dataset at https://helixweb.nih.gov/ESBL/Database/Vasopressin/). The analysis revealed only 35 vasopressin-regulated genes (of 3659) including Aqp2. Increases in RNA polymerase II binding and mRNA abundances for Aqp2 far outstripped corresponding measurements for all other genes, consistent with the conclusion that vasopressin-mediated transcriptional regulation is highly selective for Aqp2. Despite the overall selectivity of the net transcriptional response, vasopressin treatment was associated with increased RNA polymerase II binding to the promoter proximal region of a majority of expressed genes, suggesting a nearly global positive regulation of transcriptional initiation with transcriptional pausing. Thus, the overall net selectivity appears to be a result of selective control of transcriptional elongation.

Endogenous carbamylation of renal medullary proteins.

Protein carbamylation is a post-translational modification that can occur in the presence of urea. In solution, urea is in equilibrium with ammonium cyanate, and carbamylation occurs when cyanate ions react with the amino groups of lysines, arginines, protein N-termini, as well as sulfhydryl groups of cysteines. The concentration of urea is elevated in the renal inner medulla compared with other tissues. Due to the high urea concentration, we hypothesized that carbamylation can occur endogenously within the rat inner medulla. Using immunoblotting of rat kidney cortical and medullary homogenates with a carbamyl-lysine specific antibody, we showed that carbamylation is present in a large number of inner medullary proteins. Using protein mass spectrometry (LC-MS/MS) of rat renal inner medulla, we identified 456 unique carbamylated sites in 403 proteins, including many that play important physiological roles in the renal medulla [Data can be accessed at https://helixweb.nih.gov/ESBL/Database/Carbamylation/Carbamylation_peptide_sorted.html]. We conclude that protein carbamylation occurs endogenously in the kidney, modifying many physiologically important proteins.