MacLehose, Richard F.

Background Heart failure (HF) is a growing public health burden. Systemic inflammation is commonly observed in patients with HF and believed to be related to disease pathogenesis. Infection is a potential acute trigger of chronic inflammation. Our objective was to examine the relationship between infection‐related hospitalization (IRH) and HF. Methods and Results We studied beneficiaries with at least 15 months of continuous enrollment in the US‐based MarketScan databases during 2013 to 2019. We included n=152 008 patients with an inpatient or outpatient HF International Classification of Diseases, Ninth Revision/Tenth Revision ( ICD‐9/10 ) code in the primary position. Among patients with HF, IRH was identified using select ICD‐9/10 codes. We used a case‐crossover design to compare the frequency of IRH occurring within 3 months of the index HF event (case period) versus the frequency of IRH occurring 12 to 15 months before the index HF event (control period). Logistic models regressed the log‐odds of having an IRH during the case versus control periods; odds ratios (ORs; 95% CIs) are presented. Among 152 008 beneficiaries, 53% were male with a mean±SD age of 56(±11) years. The odds of having an IRH during the case (versus control) period was elevated for both the 3‐month case period (OR, 4.39 [95% CI, 4.18–4.60]), and 1‐month case period (OR, 7.39 [95% CI, 6.88–7.94]), after adjusting for the total number of hospitalizations. This relationship persisted across different types of infections. Conclusions IRH was associated with incident HF after both 1 and 3 months and may represent a modifiable risk factor for HF.

Background The immune response to infections may become dysregulated and promote myocardial damage contributing to heart failure (HF). We examined the relationship between infection‐related hospitalization (IRH) and HF, HF with preserved ejection fraction, and HF with reduced ejection fraction. Methods and Results We studied 14 468 adults aged 45 to 64 years in the ARIC (Atherosclerosis Risk in Communities) Study who were HF free at visit 1 (1987–1989). IRH was identified using select International Classification of Diseases ( ICD ) codes in hospital discharge records and was treated as a time‐varying exposure. HF incidence was defined as the first occurrence of either a hospitalization that included an ICD, Ninth Revision ( ICD‐9 ) discharge code of 428 (428.0–428.9) among the primary or secondary diagnoses or a death certificate with an ICD‐9 code of 428 or an ICD, Tenth Revision ( ICD‐10 ) code of I50 among any of the listed diagnoses or underlying causes of death. We used multivariable‐adjusted Cox proportional hazards models to assess the association between IRH and incident HF, HF with reduced ejection fraction, and HF with preserved ejection fraction. Median follow‐up time was 27 years, 55% were women, 26% were Black, mean age at baseline was 54±6 years, 46% had an IRH, and 3565 had incident HF. Hazard ratio (HR) for incident HF events among participants who had an IRH compared with those who did not was 2.35 (95% CI, 2.19–2.52). This relationship was consistent across different types of infections. Additionally, IRH was associated with both HF with reduced ejection fraction and HF with preserved ejection fraction: 1.77 (95% CI, 1.35–2.32) and 2.97 (95% CI, 2.36–3.75), respectively. Conclusions IRH was associated with incident HF, HF with reduced ejection fraction, and HF with preserved ejection fraction. IRH might represent a modifiable risk factor for HF pathophysiology.

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.

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.

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 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.

Background: Polypharmacy is highly prevalent in elderly individuals with chronic conditions, including atrial fibrillation (AF). The impact of polypharmacy on adverse outcomes and on treatment effectiveness in elderly AF patients remains unaddressed. Methods: We studied 338,810 AF patients ≥75 years of age with 1,761,660 active prescriptions [mean (SD), 5.1 (3.8) per patient] enrolled in the MarketScan Medicare Supplemental database in 2007-2015. Polypharmacy was defined as ≥5 active prescriptions at AF diagnosis based on outpatient pharmacy claims. AF treatments (oral anticoagulation, rhythm and rate control) and cardiovascular endpoints (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 endpoints and the interaction between polypharmacy and AF treatments in relation to cardiovascular endpoints. Results: Prevalence of polypharmacy was 52% (176,007 of 338,810). Patients with polypharmacy had increased risk of major bleeding [hazard ratio (HR) 1.16, 95% confidence interval (CI) 1.12, 1.20] and heart failure (HR 1.33, 95%CI 1.29, 1.36), but not of ischemic stroke (HR 0.96, 95%CI 0.92, 1.00), compared to those not with polypharmacy (Table). Polypharmacy status did not consistently modify the effectiveness of oral anticoagulants. However, rhythm control (vs. rate control) was more effective in preventing heart failure hospitalization in patients not with 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 for interaction = 0.02). Conclusion: Polypharmacy is frequent among elderly patients with AF, associated with adverse outcomes, and potentially affecting the effectiveness of AF treatments. Optimizing management of polypharmacy in elderly AF patients may lead to improved outcomes.

Introduction: 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 for the treatment of AF. 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 75 years or older diagnosed with AF in the MarketScan Medicare database between 2007-2015. Rate control was defined as use of rate control medication or atrioventricular node ablation. Rhythm control was defined by use of anti-arrhythmics, catheter ablation or cardioversion. Participants on both rate and rhythm were coded under rhythm control. We used multivariable logistic and Cox regression models to estimate 1) the association of sex and treatment strategy (within 30-day post AF diagnosis and entire follow-up) and, 2) the association of treatment strategy with incident heart failure, stroke and major bleeding. Results: Men were on average (SD) 82.5 (5.2) years old and women 83.8 (5.6) years, respectively. Women were less likely to receive rhythm control treatment as compared to men in the 30-day post AF diagnosis period (22% vs 27%), (OR 0.91, 95% CI 0.88, 0.94) and over the entire duration of follow-up (28% vs 32%) (HR 0.93, 95% CI 0.90, 0.96). Rhythm (vs. rate) control was associated with a higher risk of heart failure in women [HR 1.41, 95% CI 1.34, 1.49] than in men [HR, 1.21 95% CI 1.15, 1.28] (p for multiplicative interaction < 0.001, Table ). Sex did not modify associations between treatment and incident stroke or major bleeding events. Conclusion: Women aged 75 years and older were less likely to be prescribed rhythm control as compared to men, and experienced higher risk of heart failure than men when receiving rhythm (vs rate) control. Future studies will need to delve into the mechanisms underlying these differences.