Impaired Lung Function, Lung Disease, and Risk of Incident Dementia.

Rationale: Growing evidence suggests that compromised lung health may be linked to dementia and worsening cognitive ability. Objectives: To test the hypothesis that impaired lung function or lung disease in midlife is associated with greater risk of incident dementia and mild cognitive impairment (MCI) later in life. Methods: A total of 14,184 Atherosclerosis Risk in Communities study participants who underwent spirometry and were asked about lung health (1987-1989) were followed. Dementia and MCI were defined by hospitalization diagnosis codes (1987-2013) in the whole cohort and with adjudication among 42% who attended a comprehensive neurocognitive examination (2011-2013). Measurements and Main Results: In analysis using adjudicated outcomes, odds of dementia or MCI were higher among participants with restrictive (multivariable-adjusted odds ratio, 1.58; 95% confidence interval, 1.14-2.19) and obstructive lung disease (multivariable-adjusted odds ratio, 1.33; 95% confidence interval, 1.07-1.64), compared with those without disease or respiratory symptoms. Associations were similar in analyses restricted to nonsmokers, and present for both Alzheimer's disease-related dementia and cerebrovascular etiologies. Low FEV1% predicted and FVC% predicted were also associated with increased dementia risk. Conclusions: Midlife lung disease and reduced lung function were associated with modestly increased odds of dementia and MCI later in life. Magnitudes of association were more pronounced for restrictive impairment than for obstructive lung disease. These associations were present in smokers and nonsmokers. If the observed associations are causal, policy and public health efforts to reduce smoking and improve air quality may have the added benefit of preventing the development of dementia and MCI.

Joint Latent Class Analysis of Oral Anticoagulation Use and Risk of Stroke or Systemic Thromboembolism in Patients with Atrial Fibrillation.

BACKGROUND: Oral anticoagulation (OAC) is recommended to reduce the risk of stroke or systemic thromboembolism (TE) in atrial fibrillation (AF). In this study, we applied novel joint latent class mixed models to identify heterogeneous patterns of trajectories of OAC use and determined how these trajectories are associated with risks of thromboembolic outcomes. METHODS AND RESULTS: We used 2013-2016 claims data from a 5% random sample of Medicare beneficiaries, obtained from the Centers for Medicare and Medicaid Services. Our study sample included 16,399 patients newly diagnosed with AF in 2014-2015 who were followed for 12 months after the first AF diagnosis and filled at least one OAC prescription in this time period. OAC use was defined as the number of days covered with OACs every 30-day interval after the first AF diagnosis. We used a joint latent class mixed model to simultaneously evaluate the longitudinal patterns of OAC use and time to stroke or TE, while adjusting for age, race, CHAD2S2-VASc score and HAS-BLED score. Five classes of OAC use patterns were identified: late users (17.8%); late initiators (12.5%); early discontinuers (18.6%); late discontinuers (15.4%); and continuous users (35.6%). Compared with continuous users, the risk of stroke or TE was higher for participants in the late initiators (hazard ratio [HR] 1.73, 95% confidence interval [CI] 1.49-2.01) and late discontinuers (HR 1.23, 95% CI 1.04-1.45) classes. CONCLUSION: Late initiators and late discontinuers had a higher risk of stroke or TE than continuous users. Early initiation and continuous OAC use is important in preventing stroke and TE among patients diagnosed with AF.

Latent Classes of Adherence to Oral Anticoagulation Therapy Among Patients With a New Diagnosis of Atrial Fibrillation.

Importance: Less than half of US patients with a diagnosis of atrial fibrillation (AF) receive oral anticoagulation. Objectives: To identify patients with similar patterns of adherence to regimens of warfarin and direct oral anticoagulants (DOACs) in the first year after AF diagnosis and to evaluate associations between patient characteristics and membership in latent classes of adherence. Design, Setting, and Participants: This retrospective cohort study used 2013 to 2016 Medicare claims data to identify 7491 patients with a new diagnosis of AF in 2014 to 2015 who initiated warfarin after AF diagnosis and 9478 patients with a new diagnosis of AF in 2014 to 2015 who initiated DOAC treatment after AF diagnosis, for a total of 16 969 Medicare beneficiaries. Participants were followed up for 12 months after AF diagnosis. Statistical analysis was performed from February 1 to November 30, 2018. Exposures: Treatment with warfarin or DOAC after AF diagnosis. Main Outcomes and Measures: The main outcome was the proportion of days that patients received warfarin or DOAC, measured in 30-day intervals after AF diagnosis. Independent variables included patient demographic characteristics, socioeconomic status, region of residence, and clinical characteristics. Latent class mixed models were used to identify latent classes of warfarin and DOAC adherence, and polytomous logistic regression was used to assess the association between patient characteristics and membership in each latent class. Results: Among the 7491 patients receiving warfarin (4348 women), the mean (SD) age was 76.0 (10.0) years; among the 9478 patients receiving DOAC (5496 women), the mean (SD) age was 77.0 (8.5) years. Four latent classes of patients were identified based on warfarin adherence: late initiators (980 [13%]), early initiators who discontinued therapy at months 1 to 3 (1297 [17%]) or at months 5 to 10 (735 [10%]), and continuously adherent patients (4479 [60%]). Four latent classes of patients were also identified based on DOAC adherence: patients who initiated DOAC in months 1 to 5 (1368 [14%]) or months 6 to 11 (800 [8%]), patients with suboptimal and decreasing adherence (2267 [24%]), and continuously adherent patients (5043 [53%]). Membership in latent classes of warfarin adherence was significantly associated with sex, eligibility for Medicaid and income subsidy, region of residence, CHA2DS2-VASc (cardiac failure or dysfunction, hypertension, age 65-74 [1 point] or ≥75 years [2 points], diabetes, and stroke, transient ischemic attack or thromboembolism [2 points]-vascular disease, and sex category [female]) risk score, and HAS-BLED (hypertension, abnormal renal and liver function, stroke, bleeding, labile international normalized ratio, elderly, and drugs or alcohol) score. Membership in latent classes of DOAC adherence was significantly associated with race/ethnicity, region of residence, HAS-BLED score, and use of antiarrhythmic medications. Conclusions and Relevance: This study found that, among patients who initiated anticoagulation therapy, 40% of those who initiated warfarin therapy and 47% of those who initiated DOAC treatment did not continuously adhere to therapy in the first year after AF diagnosis. Identifying longitudinal patterns of warfarin and DOAC adherence and the factors associated with them provides suggestions for the design of targeted strategies to mitigate suboptimal oral anticoagulation use.

Effectiveness and Safety of Restarting Oral Anticoagulation in Patients with Atrial Fibrillation after an Intracranial Hemorrhage: Analysis of Medicare Part D Claims Data from 2010-2016.

BACKGROUND: In patients with atrial fibrillation (AF) who survive an anticoagulant-related intracranial hemorrhage (ICH), the benefits of restarting oral anticoagulation (OAC) remain unclear. OBJECTIVE: In this study, we sought to determine the effectiveness and safety associated with resumption of OAC in atrial fibrillation patients who survive an ICH. METHODS: Using 2010-2016 Medicare claims data, we identified patients with non-valvular AF who experienced an OAC-related ICH and survived at least 6 weeks after the ICH (n = 1502). The primary outcomes included the composite of ischemic stroke and transient ischemic attack (TIA), thromboembolism (TE), a composite of ischemic stroke/TIA and TE, recurrent ICH, and all-cause mortality. We constructed Cox proportional hazard models to evaluate the association between post-ICH OAC resumption, which was measured in a time-dependent manner, and the risk of primary outcomes, while controlling for a comprehensive list of covariates. RESULTS: Among patients who survived an ICH, 69% reinitiated OAC within 6 weeks of the event, and among those who resumed OAC, 83% restarted warfarin. There was no significant difference in the risk of ischemic stroke/TIA (hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.62-1.21), TE (HR 0.85, 95% CI 0.55-1.32), and ischemic stroke/TIA/TE (HR 0.81, 95% CI 0.61-1.07) between post-ICH OAC use and non-use. Post-ICH OAC use was associated with a lower risk of recurrent ICH (HR 0.62, 95% CI 0.41-0.95) and all-cause mortality (HR 0.48, 95% CI 0.37-0.62) compared with non-OAC use. CONCLUSIONS: In AF patients who survived an ICH, restarting OAC was not associated with a greater risk of recurrent ICH. Evidence from randomized controlled studies is needed to further clarify the clinical benefit of restarting OAC in this high-risk population. Further evaluation of which individuals benefit from restarting OAC is also needed to provide more clinical guidance.

Regional Gray Matter Density Associated With Fast-Paced Walking in Older Adults: A Voxel-Based Morphometry Study.

BACKGROUND: Walking speed during fast-paced walking task has been associated with cognitive function. It is unclear what underlying brain structures are related to fast-paced walking. We investigated the association of gray matter (GM) density with fast-paced walking speed and usual-paced walking speed. METHODS: We collected data from 284 older adults from a subset of the Health, Aging, and Body composition study (mean age = 83 [SD = 2.8], 58% women, 41% black). Voxel-wise analyses on magnetic resonance imaging data identified regions of the brain where GM density was associated with fast-paced walking speed. We then extracted GM density for all identified regions and modeled the association with fast-paced walking speed after adjusting for demographic factors, clinical factors, and cognitive function. Analyses were repeated for usual-paced walking. Regions with beta coefficients ≥0.3 m/s were considered to be meaningfully correlated. RESULTS: GM density of clusters from cortical regions in the right middle and superior frontal gyrus, right postcentral gyrus, and left superior temporal gyrus were positively correlated with fast-paced walking speed in adjusted models. Adjustment for cognitive function had little impact on the findings. Caudate was correlated with usual paced walking speed at coefficient ≥0.3 m/s after adjustment of demographic factors and clinical factors, but not after further adjustment of cognitive function. CONCLUSIONS: Fast-paced walking speed was correlated with GM density of right middle and superior frontal gyrus, right postcentral gyrus, and left superior temporal gyrus, and could potentially provide evidence about subclinical structural change of brain related to aging.

Impact of direct-to-consumer drug advertising during the Super Bowl on drug utilization.

BACKGROUND: Direct-to-consumer advertising (DTCA) of prescription drugs impacts patients' requests for medications, and clinician prescribing. However, the impact of DTCA during the Super Bowl has not been previously described. OBJECTIVE: Evaluate the impact of prescription drug DTCA during the Super Bowl on drug utilization using 2014-2016 Medicare data. METHODS: Efinaconazole was advertised during Super Bowls XLIX (02/01/2015) and L (02/07/2016). The number of prescriptions for efinaconazole and for a comparator drug, tavaborole, were calculated in 31-day intervals from July 2014-December 2016. Interrupted time-series analysis models were created to test changes in trends of prescriptions for efinaconazole and tavaborole. RESULTS: Following Super Bowl XLIX, the number of prescriptions per 100,000 Medicare beneficiaries increased by 91% for efinaconazole, and 275% for tavaborole. After Super Bowl L, the number of prescriptions increased significantly for efinaconazole (p-value<0.001), but not for tavaborole (p = 0.70). Interrupted time-series analyses estimated that, in the absence of DTCA during Super Bowl XLIX, prescriptions for efinaconazole would have increased by 40%, instead of the observed 91%. For tavaborole, prescriptions would have increased by 90% instead of 275%. CONCLUSIONS: DTCA during the Super Bowl resulted in sharp increases in utilization of the prescription drug advertised, which supports further regulation of DTCA.

Race/Ethnicity and Sex-Related Differences in Direct Oral Anticoagulant Initiation in Newly Diagnosed Atrial Fibrillation: A Retrospective Study of Medicare Data.

BACKGROUND: Atrial fibrillation (AF) is the most common heart rhythm disorder and is associated with a 5-fold increased risk of ischemic stroke. Racial/ethnic minorities and women with AF have higher rates of stroke compared to white individuals and men respectively. Oral anticoagulation reduces the risk of stroke, yet prior research has described racial/ethnic and sex-based variation in its use. We sought to examine the initiation of any oral anticoagulant (warfarin or direct-acting oral anticoagulants, DOACs) by race/ethnicity and sex in patients with incident, non-valvular AF. Further in those who initiated any anticoagulant, we examined DOAC vs. warfarin initiation by race/ethnicity and sex. METHODS: We used claims data from a 5% sample of Medicare beneficiaries to identify patients with incident AF from 2012 to 2014, excluding those without continuous Medicare enrollment. We used logistic regression to assess the association between race/ethnicity (white, black, Hispanic), sex, and oral anticoagulant initiation (any, warfarin vs. DOAC), adjusting for sociodemographics, medical comorbidities, stroke and bleeding risk. RESULTS: The cohort of 42,952 patients with AF included 17,935 women, 3282 blacks, and 1958 Hispanics. Overall OAC initiation was low (49.2% whites, 48.1% blacks, 47.5% Hispanics, 48.1% men, and 51.5% women). After adjusting, blacks (odds ratio (OR) 0.84; 95% CI, 0.78-0.91) were less likely than whites to initiate any oral anticoagulant with no difference observed between Hispanics and whites (OR 0.92; 95% CI, 0.83-1.01). Women were less likely than men to initiate any oral anticoagulant, OR 0.59 (95% CI 0.55-0.64). Among initiators of oral anticoagulation, DOAC use was low (35.8% whites, 29.3% blacks, 40.0% Hispanics, 41.6% men, and 42.4% women). After adjusting, blacks were less likely to initiate DOACs than whites, OR 0.75 (95% CI 0.66-0.85); the odds of DOAC initiation did not differ between Hispanic and white patients or between men and women. CONCLUSION: In a national cohort of Medicare beneficiaries with newly-diagnosed AF, overall oral anticoagulant initiation was lower in blacks and women, with no difference observed by Hispanic ethnicity. Among oral anticoagulant initiators, blacks were less likely to initiate novel DOACs, with no differences identified by Hispanic ethnicity or sex. Identifying modifiable causes of treatment disparities is needed to improve quality of care for all patients with AF.

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.

Corrigendum to 'Association of sickle cell trait with measures of cognitive function and dementia in African Americans' eNeurologicalSci, Vol. 16 (2019), 100,201.

[This corrects the article DOI: 10.1016/j.ensci.2019.100201.].

Trajectories of Oral Anticoagulation Adherence Among Medicare Beneficiaries Newly Diagnosed With Atrial Fibrillation.

Background Only 50% of atrial fibrillation ( AF ) patients recommended for oral anticoagulation ( OAC ) use these medications, and less than half of them adhere to OAC . In a cohort of Medicare beneficiaries newly diagnosed with AF , we identified groups of patients with similar trajectories of OAC use and adherence, and evaluated patient characteristics affecting group membership. Methods and Results We selected continuously enrolled Medicare Part D beneficiaries with first AF diagnosis in 2014 to 2015 (n=34 898). We calculated the proportion of days covered with OAC over the first 12 months after diagnosis and identified OAC adherence trajectories using group-based trajectory models. We constructed multinomial logistic regression models to evaluate how demographics, system-level factors, and clinical characteristics were associated with group membership. We identified 4 trajectories of OAC adherence: patients who never used OAC (43.8%), late OAC initiators (7.6%), early OAC discontinuers (8.9%), and continuously adherent patients (40.1%). Predictors such as sex, black race, residence in the South, or HAS - BLED score were associated with not only OAC use, but also the timing of initiation and the likelihood of discontinuation. For example, HAS - BLED score ≥4 was associated with a higher likelihood of not using OAC (odds ratio 1.35; 95% CI , 1.14-1.62), of late initiation (1.55; 95% CI , 1.11-2.05), and of early discontinuation (odds ratio 1.35; 95% CI , 1.01-1.84). Conclusions We identified 4 distinct trajectories of OAC adherence after first AF diagnosis, with <45% of newly diagnosed AF patients belonging to the trajectory group characterized by continuous OAC adherence. Trajectories were associated not only with demographic and clinical characteristics but also with regional factors.

Association of sickle cell trait with measures of cognitive function and dementia in African Americans.

OBJECTIVE: The incidence and prevalence of cognitive decline and dementia are significantly higher among African Americans compared with non-Hispanic Whites. The aim of this study was to determine whether inheritance of the sickle cell trait (SCT) i.e. heterozygosity for the sickle cell mutation increases the risk of cognitive decline or dementia Among African Americans. METHODS: We studied African American participants enrolled in the Atherosclerosis Risk in Communities study. SCT genotype at baseline and outcome data from cognitive assessments at visits 2, 4 and 5, and an MRI performed at visit 5 were analyzed for the association between SCT and risk of cognitive impairment and/or dementia. RESULTS: There was no significant difference in risk factors profile between participants with SCT (N = 176) and those without SCT (N = 2532). SCT was not independently associated with a higher prevalence of global or domain-specific cognitive impairment at baseline or with more rapid cognitive decline. Participants with SCT had slightly lower incidence of dementia (HR = 0.63 [0.38, 1.05]). On the other hand, SCT seems to interact with the apolipoprotein E ε4 risk allele resulting in poor performance on digit symbol substitution test at baseline (z-score = -0.08, Pinteraction = 0.05) and over time (z-score = -0.12, Pinteraction = 0.04); and with diabetes mellitus leading to a moderately increased risk of dementia (HR = 2.06 [0.89, 4.78], Pinteraction = 0.01). CONCLUSIONS: SCT was not an independent risk factor for prevalence or incidence of cognitive decline or dementia, although it may interact with and modify other putative risk factors for cognitive decline and dementia.

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.