Norby, Faye L.

Introduction: Isolated cases of liver injury associated with the use of non-vitamin K antagonist oral anticoagulants (NOACs) have been reported. However, the comparative incidence of liver injury in users of different oral anticoagulants is unknown. Methods: We studied 113,717 patients (mean age 70, 39% women) with non-valvular atrial fibrillation (AF) included in the MarketScan® Commercial and Medicare Supplemental databases with a first prescription for oral anticoagulation after November 4, 2011, followed through December 31, 2014. Of these, 56,879 initiated warfarin, 17,286 initiated dabigatran, 30,347 initiated rivaroxaban, and 9,205 initiated apixaban. Liver injury hospitalizations were identified using selected inpatient diagnostic codes. Multivariable Cox models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) of liver injury by anticoagulant type. Results: During a median follow-up of 12 months, 960 hospitalizations with liver injury were identified. Rates of liver injury hospitalization (per 1000 person-years) by oral anticoagulant were 9.0 (warfarin), 4.0 (dabigatran), 6.6 (rivaroxaban), and 5.6 (apixaban). After multivariable adjustment, rates of liver injury hospitalization were lower in initiators of NOACs compared to warfarin: HR (95%CI) of 0.57 (0.46, 0.71), 0.88 (0.75, 1.03) and 0.70 (0.50, 0.97) for initiators of dabigatran, rivaroxaban, and apixaban, respectively (Table). Compared to dabigatran initiators, rivaroxaban initiators had a 56% increased risk of liver injury hospitalization (HR 1.56, 95%CI 1.22, 1.99). In addition to type of anticoagulant, prior liver, gallbladder, and kidney disease, cancer, anemia, heart failure, and alcoholism significantly predicted liver injury hospitalization. Conclusions: Among patients with non-valvular AF, NOACs were associated with lower risk of liver injury hospitalization compared to warfarin, with dabigatran showing the lowest risk.

AbstractBackgroundRecent evidence indicates that abnormal P‐wave parameters (PWPs)—ECG markers of atrial myopathy—are associated with incident dementia, independent of atrial fibrillation (AF) and clinical ischemic stroke. However, the mechanisms remain unclear and may include subclinical vascular brain injury. Hence, we evaluated the association of abnormal PWPs with brain MRI correlates of vascular brain injury in the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC‐NCS).MethodsARIC‐NCS participants who underwent 3T brain MRI scans in 2011–2013 were included. PWPs were measured from standard 12‐lead ECGs. Brain MRI outcomes included cortical infarcts, lacunar infarcts, cerebral microhemorrhages, brain volumes, and white matter disease (WMD) volume. We used weighted multivariable logistic and linear regression to evaluate the associations of abnormal PWPs with brain MRI outcomes.ResultsAmong 1715 participants (mean age, 76.1 years; 61% women; 29% Black), 797 (46%) had ≥1 abnormal PWP. After multivariable adjustment, including adjusting for prevalent AF, abnormal P‐wave terminal force in lead V1 (aPTFV1) and prolonged P‐wave duration (PPWD) were associated with increased odds of both cortical (OR 1.41; 95% CI, 1.14 to 1.74 and OR 1.30; 95% CI, 1.04 to 1.63, respectively) and lacunar infarcts (OR 1.36; 95% CI, 1.15 to 1.63 and OR 1.37; 95% CI, 1.15 to 1.65, respectively). Advanced interatrial block (aIAB) was associated with higher odds of subcortical microhemorrhage (OR 2.04; 95% CI, 1.36 to 3.06). Other than a significant association between aPTFV1 with lower parietal lobe volume, there were no other significant associations with brain or WMD volume.ConclusionIn this exploratory analysis of a US community‐based cohort, ECG surrogates of atrial myopathy are associated with a higher prevalence of brain infarcts and microhemorrhage, suggesting subclinical vascular brain injury as a possible mechanism underlying the association of atrial myopathy with dementia.

Background: Women and African Americans with atrial fibrillation (AF) experience higher rates of stroke compared to men and white AF patients, respectively. However, sex and race differences for cardiovascular outcomes other than stroke have not been specifically evaluated in patients with AF. Methods: We studied patients with AF in the Optum Clinformatics database between 2009 and 2015 with at least 6 months of enrollment before AF diagnosis. The Optum Clinformatics database includes medical and pharmacy claims and sociodemographic information on privately insured and Medicare Advantage enrollees throughout the US. Endpoints (hospitalizations for ischemic stroke, heart failure (HF), myocardial infarction (MI)) and covariates were defined using validated algorithms. Multivariable Cox models were used to study the association of race and sex with endpoints of interest. Results: The analysis included 380,636 eligible participants (mean age 73, women 45%). Of them, 82% were white, 9% African American, 7% Hispanic and 2% Asian American. During a mean follow-up of 23 months, 7,235 suffered ischemic stroke, 17,258 HF, and 5,585 MI. Crude rates of ischemic stroke and HF were higher in women than men, while men had higher rates of MI than women (Table). African Americans and Hispanics had higher rates of all studied outcomes than whites and Asian Americans. In models including age, sex, race, education and CHA 2 DS 2 -VASc score, women had higher risk of ischemic stroke and lower risk of HF and MI compared to men. Compared to whites, African Americans had 1.4 times the rate of HF and stroke, and 1.1 times the rate of MI, while Asian Americans had 16% lower rates of HF. No major differences were observed between rates in whites and Hispanics (Table). Conclusion: In a large insured population of patients with AF, we observed differences in rates of selected cardiovascular outcomes by sex and race. Additional research should explore the mechanisms underlying these differences and develop strategies to eliminate them.

AbstractAimWe investigate if periodontal disease is prospectively associated with cerebrovascular and neurodegenerative markers of dementia and Alzheimer's pathology.Materials and MethodsN = 1306 participants (Visit 5 mean age = 76.5 [standard deviation = 5.4] years) in the Atherosclerosis Risk in Communities study with completed dental exams at Visit 4 underwent brain magnetic resonance imaging scans at Visit 5 while N = 248 underwent positron emission tomography scans. Participants were classified as edentulous or, among the dentate, by the modified Periodontal Profile Class. Brain volumes were regressed on periodontal status in linear regressions. Cerebrovascular measures and β‐amyloid positivity were regressed on periodontal status in logistic regressions.ResultsPeriodontal disease was not associated with brain volumes, microhaemorrhages, or elevated β‐amyloid. Compared with periodontally healthy individuals, odds ratios [95% confidence interval] for all‐type infarcts were 0.37 [0.20, 0.65] for severe tooth loss and 0.56 [0.31, 0.99] for edentulous participants.ConclusionsWithin the limitations of this study, periodontal disease was not associated with altered brain volumes, microhaemorrhages, or β‐amyloid positivity. Tooth loss was associated with lower odds of cerebral infarcts.

Abstract 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 2007-2015. 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.

Background: Current guidelines recommend oral anticoagulation for the prevention of stroke in most patients with atrial fibrillation (AF). Direct oral anticoagulants (DOACs) are associated with lower risk of ischemic stroke and intracranial bleeding than warfarin and, therefore, may reduce risk of dementia among patients with AF. Hypothesis: AF patients initiating DOACs for stroke prevention will have lower risk of dementia than patients initiating warfarin. Methods: We used data from two US healthcare claim databases, MarketScan (2007-2015) and Optum Clinformatics (2009-2015). Using validated algorithms, we identified patients with AF who initiated oral anticoagulation. Dementia was defined as having an International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code of 290.xx, 294.xx, or 331.0. Comorbidities and use of other medications were defined based on inpatient, outpatient, and pharmacy claims. We performed a series of head-to-head comparisons of different oral anticoagulants (warfarin, dabigatran, rivaroxaban, and apixaban) in propensity score-matched cohorts. In each database, multivariable-adjusted Cox regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for incident dementia for each comparison of propensity score-matched cohorts, adjusting for age, sex, comorbidities, use of other medications, and markers of socioeconomic status (in the Optum database only). We meta-analyzed database-specific results using a random-effects model. Results: The analysis included 307,099 AF patients from the MarketScan database and 161,346 from the Optum database, of which 6,572 and 4,391 respectively had a diagnosis of incident dementia. Mean follow up ranged between 0.7 to 2.3 years and incident of diagnosed dementia between 7 to 14 cases per 1000 person-years across different oral anticoagulant initiator groups. Patients initiating DOACs had a lower risk of incident 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 risk of incident dementia comparing DOAC user groups (dabigatran vs. rivaroxaban: HR 1.02, 95%CI 0.79, 1.32; dabigatran vs. apixaban: HR 0.92, 95%CI 0.63, 1.36; apixaban vs. rivaroxaban: HR 1.01, 95%CI 0.86, 1.19). Conclusions: Patients with AF initiating DOACs experienced lower rates of incident dementia than warfarin users. No obvious benefit was observed for any particular DOAC in relation to dementia rates.

Background: Oral anticoagulants (OACs) are recommended for AF patients for the prevention of thromboembolic events, including stroke. Stroke risk stratification scores (e.g., CHA 2 DS 2 -VASc) are used to tailor therapeutic recommendations for patients in different risk groups. However, these were derived before the advent of direct OACs. At present, there is no tool that estimates a patient’s stroke risk, given their individual characteristics, by type of OAC. Methods: We used healthcare utilization data from two independent US databases (MarketScan and Optum) to construct and validate a predictive model of ischemic stroke in patients with AF initiating OACs. Patients with non-valvular AF initiating OACs were identified from the MarketScan data for years 2007-2015. Using bootstrapping methods and backward selection of 44 candidate variables, we developed a model which selected variables predicting stroke. The final model was validated in patients with non-valvular AF in the Optum Clinformatics database in the period 2009-2015. Results: Among 135,523 patients with AF initiating OAC in the MarketScan dataset, 2,028 experienced an ischemic stroke after anticoagulant initiation. The stepwise model identified 15 variables (including type of OAC) associated with ischemic stroke (Table). The discrimination (c-statistic) of the model was adequate [0.68, 95% confidence interval (CI) 0.66-0.70], showing excellent calibration (χ 2 = 7.7 p=0.57). The model was then applied to the 84,549 AF patients in the Optum data set (1408 stroke events). The model showed similar discrimination (c-statistic 0.67, 95%CI 0.65-0.70) and calibration (χ 2 = 12.8 p=0.17). However, previously-developed predicted models had similar discriminative ability (CHA 2 DS 2 -VASc 0.67, 95%CI 0.65-0.68; ATRIA 0.67, 95%CI 0.65-0.68) Conclusion: A novel model using extensive administrative healthcare data for the identification of patients at higher risk of ischemic stroke by type of anticoagulant did not perform better than established simple models.

Background: Periodontal disease (PD) is associated positively with neurocognitive outcomes. Few studies have investigated the relationship between PD and indicators of brain aging and vascular changes. Hypothesis: PD is associated with greater cerebral small vessel disease, lower total and regional brain volumes and elevated β-amyloid (Aβ) deposition. Methods: We included 6,793 participants who received full-mouth periodontal examinations and tooth counts at Visit 4 (1996-1998) of the Atherosclerosis Risk in Communities Study. We used a modified 3-level version of the Periodontal Profile Class to categorize PD based on severity and extent of gingival inflammation and tissue loss. Among participants who attended Visit 5 (2011-2013), n=1,306 received a brain MRI and n=248 received a PET scan. Total brain volume, Alzheimer’s disease signature volume, and presence of microhemorrhages and cerebral infarctions were ascertained via 3T MRI; Aβ deposition was assessed from PET. We regressed brain volumes on baseline PD status using weighted multivariable linear regression. Presence of cerebrovascular microhemorrhages, infarctions, or elevated Aβ (standardized uptake value ratio>1.2) were regressed on PD category using logistic models. We examined the interaction between Apolipoprotein E ε4 ( APOE ) allele possession and PD categories on the Aβ outcome. Results: Prevalence of baseline periodontal disease was 73% (959/1306) and 87% (206/248) among the MRI and PET subgroups, respectively. PD was not associated with volumetric brain measures nor microhemorrhages. PD was inversely associated with the odds of subcortical and lacunar infarctions. PD and Aβ were not associated in main effect or interaction analyses, although there was a notably stronger association among carriers of APOE . Conclusion: PD was not associated with altered brain structure, cerebral microhemorrhages or elevated Aβ deposition. Counter to the hypothesis, PD and complete tooth loss were inversely associated with cerebral infarctions.

Background: Elevated carotid intima-media thickness (cIMT) and presence of carotid plaque are markers of atherosclerosis, which may be linked to structural brain injury. Using data from the ARIC-NCS cohort, we tested the hypotheses that greater cIMT and presence of carotid plaque at late midlife were each associated with presence of infarcts (lacunar and cortical) and cerebral microbleeds (lobar and subcortical), greater white matter hyperintensity (WMH) volume, and smaller regional brain volumes in late life. Methods: We included 1,795 ARIC participants who had carotid ultrasounds in 1990-92 and brain MRI scans in 2011-13. Weighted linear regression was used for continuous (brain volume) outcomes, and weighted logistic regression for dichotomous outcomes (infarcts and cerebral microbleeds). Results: Participants were aged 57±6 years at baseline, 57% were female, and 23% were Black. Mean ± SD follow-up was 21±1 years. After multivariable adjustments, the highest quintile of cIMT in late midlife was associated with smaller deep grey matter volume (β [95% CI]: -0.11 [-0.22, -0.01]) and cortical volume in a temporal-parietal meta region of interest (ROI) (β [95% CI]: -0.10 [-0.20, -0.01]) in late life (Table). At baseline, 473 (26%) participants had carotid plaque present on their carotid ultrasound. Similar to cIMT, those with carotid plaque had smaller regional brain volumes than those without carotid plaque present (βs [95% CIs]: -0.05 [-0.12, 0.03] and -0.06 [-0.13, 0.01] for deep grey matter and temporal-parietal meta ROI volumes, respectively). No significant relations were observed with WMH volume, or the presence of any infarcts or cerebral microbleeds. Conclusion: Greater midlife cIMT and presence of carotid plaque were associated with smaller deep grey matter volume and cortical volume in a temporal-parietal meta ROI in later life. Contrary to our hypothesis, associations between midlife subclinical atherosclerosis and markers of vascular brain injury in later life were null.

Introduction: We recently reported that abnormal P-wave indices (PWI)—ECG markers of atrial cardiomyopathy (AC)—are associated with an increased risk of dementia, independent of atrial fibrillation (AF) and clinical ischemic stroke. The mechanisms, however, remain unclear, but may include silent ischemia. Hypothesis: Abnormal PWI are associated with higher prevalence of cortical infarcts on MRI, suggesting cardioembolism as a potential mechanism. Methods: ARIC-NCS participants (mean age, 72.2±5.3 years; 60% women; 29% black) who underwent 3T brain MRI scans in 2011-2013 were included. Abnormal PWI included P-wave terminal force in lead V1 [(PTFV1) defined as ≥4000 μV*ms] and P-wave duration [(PWD) defined as >120 ms], which were measured from standard 12-lead ECGs. Brain MRI outcomes included cortical infarcts, cerebral microbleeds (CMB), and markers of small vessel disease [white matter hyperintensities (WMH) and lacunar infarcts]. We used weighted multivariable logistic and linear regression analyses. Results: Of the 1,850 participants, 464 had abnormal PTFV1 and 415 had prolonged PWD. After multivariable adjustment including AF, abnormal PTFV1 and PWD were significantly associated with 26-44% increased odds of cortical and lacunar infarcts (Table) . Although PWD was associated with CMB in Model 1, the association was no longer significant after multivariable adjustment. Finally, abnormal PWIs were not associated with WMH after adjusting for stroke and AF (P >0.5). Conclusions: Abnormal PWI are associated with higher prevalence of cortical infarcts, suggesting cardioembolism with silent ischemia as a possible mechanism underlying the association of AC with dementia. More research is needed to evaluate other mechanisms such as cerebral small vessel disease.