Optimization of nitrogen removal and microbial mechanism of a hydrogen-based membrane biofilm reactor.

The hydrogen-based membrane biofilm reactor (H2-MBfR) is an emerging biological nitrogen removal technology characterized by high efficiency, energy-saving capability, and environmental friendliness. The technology achieves denitrification and denitrogenation of microorganisms by passing hydrogen as an electron donor from inside to outside through the hollow fibre membrane module, and eventually the hydrogen reachs the biofilm attached to the surface of the fibre membrane. H2-MBfR has obtained favourable outcomes in the treatment of secondary biochemical effluent and low concentration nitrogen polluted water source. The experiment was optimized by s single-factor testing and response surface methodology-based optimization (RSM), and the optimal operational conditions were obtained as follows: an influent flow rate of 2 mL/min, hydrogen pressure of 0.04 MPa, and influent nitrate concentration of 24.29 mg/L. Under these conditions, a high nitrate removal rate of 98.25% was achieved. In addition, Proteobacteria and Bacteroidetes were the dominant bacteria in all stages, and the genus Hydrogenophaga was sufficiently enriched, occurring at 13.0%-49.0% throughout the reactor operation. Furthermore, the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway for nitrate reduction and inorganic carbon utilization by microorganisms in the H2-MBfR was explored through comparison with the KEGG database. The results provided a mechanistic explanation for the denitrification and carbon sequestration capacity of the H2-MBfR.

G protein-coupled estrogen receptor 1 deficiency impairs adult hippocampal neurogenesis in mice with schizophrenia.

OBJECTIVE: This study aimed to confirm that G protein-coupled estrogen receptor 1 (GPER1) deficiency affects cognitive function by reducing hippocampal neurogenesis via the PKA/ERK/IGF-I signaling pathway in mice with schizophrenia (SZ). METHODS: Mice were divided into four groups, namely, KO Con, WT Con, KO Con, and WT SZ (n = 12 in each group). All mice were accustomed to the behavioral equipment overnight in the testing service room. The experimental conditions were consistent with those in the animal house. Forced swimming test and Y-maze test were conducted. Neuronal differentiation and maturation were detected using immunofluorescence and confocal imaging. The protein in the PKA/ERK/IGF-I signaling pathway was tested using Western blot analysis. RESULTS: GPER1 KO aggravated depression during forced swimming test and decreased cognitive ability during Y-maze test in the mouse model of dizocilpine maleate (MK-801)-induced SZ. Immunofluorescence and confocal imaging results demonstrated that GPER1 knockout reduced adult hippocampal dentate gyrus neurogenesis. Furthermore, GPER1-KO aggravated the hippocampal damage induced by MK-801 in mice through the PKA/ERK/IGF-I signaling pathway. CONCLUSIONS: GPER1 deficiency reduced adult hippocampal neurogenesis and neuron survival by regulating the PKA/ERK/IGF-I signaling pathway in the MK-801-induced mouse model of SZ.

Immp2l Mutation Induces Mitochondrial Membrane Depolarization and Complex III Activity Suppression after Middle Cerebral Artery Occlusion in Mice.

OBJECTIVE: We previously reported that mutations in inner mitochondrial membrane peptidase 2-like (Immp2l) increase infarct volume, enhance superoxide production, and suppress mitochondrial respiration after transient cerebral focal ischemia and reperfusion injury. The present study investigated the impact of heterozygous Immp2l mutation on mitochondria function after ischemia and reperfusion injury in mice. METHODS: Mice were subjected to middle cerebral artery occlusion for 1 h followed by 0, 1, 5, and 24 h of reperfusion. The effects of Immp2l+/- on mitochondrial membrane potential, mitochondrial respiratory complex III activity, caspase-3, and apoptosis-inducing factor (AIF) translocation were examined. RESULTS: Immp2l+/- increased ischemic brain damage and the number of TUNEL-positive cells compared with wild-type mice. Immp2l+/- led to mitochondrial damage, mitochondrial membrane potential depolarization, mitochondrial respiratory complex III activity suppression, caspase-3 activation, and AIF nuclear translocation. CONCLUSION: The adverse impact of Immp2l+/- on the brain after ischemia and reperfusion might be related to mitochondrial damage that involves depolarization of the mitochondrial membrane potential, inhibition of the mitochondrial respiratory complex III, and activation of mitochondria-mediated cell death pathways. These results suggest that patients with stroke carrying Immp2l+/- might have worse and more severe infarcts, followed by a worse prognosis than those without Immp2l mutations.

Validation and meaningful within-patient change in work productivity and activity impairment questionnaire (WPAI) for episodic or chronic migraine.

BACKGROUND: No available studies demonstrate validity and meaningful change thresholds of Work Productivity and Activity Impairment (WPAI) questionnaire in patients with migraine. In this post-hoc analysis, we assessed reliability, validity, responsiveness, and meaningful within-patient change from baseline to Month 3 for Work Productivity and Activity Impairment (WPAI) domain scores in patients with episodic migraine (EM) or chronic migraine (CM). METHOD: The Phase 3, multicenter, randomized, double-blind, placebo-controlled CONQUER study (NCT03559257, N = 462) enrolled patients with EM or CM who failed two to four categories of prior preventive medication in past ten years. The analyses were performed for WPAI domain scores (absenteeism, presenteeism, overall work productivity, and non-work-related activity impairment). Migraine Specific Quality of Life Questionnaire version 2.1 (MSQv2.1) domain scores (Role Function-Restrictive [RFR] and Role Function-Preventive [RFP]), and monthly migraine headache days were used as anchors. Responder criteria were changes from baseline to Month 3 for each of these anchors and were defined as: increase in MSQ-RFR by ≥ 25.71 points and MSQ-RFP by ≥ 20.00 points and a 50% reduction in monthly migraine headache days. Assessments were performed for overall population, and patients with EM or CM. The meaningful change threshold was determined based on Youden index, Phi coefficient and sensitivity. RESULTS: Of 462 randomized patients, 444 who completed WPAI questionnaire were included in post-hoc analysis. Test-retest reliability over 3 months in a stable subgroup revealed moderate correlations for non-work-related Activity Impairment (ICC = 0.446) presenteeism (ICC = 0.438) and a fair correlation for overall work productivity loss (ICC = 0.360). At baseline, all correlations between WPAI domain scores and continuous anchor variables exceeded recommended threshold of ≥ 0.30, except for WPAI domain scores with number of monthly migraine headache days. Patients achieving pre-specified responsiveness thresholds for monthly migraine headache days, and MSQ-RFP, MSQ-RFR from baseline to Month 3 (responders) showed significant improvements in WPAI domain scores compared with non-responders (P < 0.001). The meaningful change thresholds of -20 (% unit) were identified for WPAI domain scores. CONCLUSION: In conclusion, WPAI has sufficient validity, reliability, responsiveness, and appropriate interpretation standards to assess the impact of EM or CM on presenteeism and overall work productivity loss and non-work-related activity impairment. TRIAL REGISTRATION: NCT number of CONQUER study, NCT03559257.

Annual indirect costs savings in patients with episodic or chronic migraine: a post-hoc analysis of phase 3 galcanezumab clinical trials in the United States.

BACKGROUND: Galcanezumab (GMB) improved quality-of-life and reduced disability of patients with episodic (EM) and chronic migraine (CM) in Phase 3 trials. AIM: To estimate indirect cost savings associated with GMB treatment in patients with migraine in the United States (US). METHODS: We analyzed data of patients from the US from three randomized, Phase 3, double-blind, placebo (PBO)-controlled GMB studies: EVOLVE-1 and EVOLVE-2 (EM patients), REGAIN (CM patients). Annual indirect costs were calculated using items of the Migraine Disability Assessment (MIDAS) questionnaire: lost time/productivity at work/school, household work, and leisure time. All costs were annualized and expressed in 2019 US dollars. While the main analysis considered lost time/productivity at work/school and household work as a full day, a sensitivity analysis was performed by discounting them by half. For EM, annual indirect costs savings were estimated using mixed model repeated measures analysis. For CM, ANCOVA models were used to estimate annual indirect costs savings as change from baseline. RESULTS: The analysis included 805 patients with EM (mean age = 41.4 years; PBO = 534; GMB = 271) and 423 patients with CM (mean age = 38.9 years; PBO = 279; GMB = 144). Compared to PBO, GMB significantly reduced annual indirect costs among patients with EM at 3 months (least square mean [95% confidence interval] work/school = $1,883.6 [603.64-3,163.65], p = .0040, household work = $628.9 [352.95-904.88], p <.0001, and leisure activity = $499.17 [42.36-955.98], p = .0323) and 6 months (work/school = $2,382.29 [1,065.48-3,699.10], p = .0004, household work = $559.45 [268.99-849.90], p = .0002, and leisure activity = $753.81 [334.35-1,173.27], p = .0004), whereas a significant difference was not observed among patients with CM. Sensitivity analysis results were similar to primary analysis results. CONCLUSIONS: GMB treatment versus PBO resulted in significantly greater indirect cost savings in patients with EM through improved productivity at work/school, household work, and leisure days. Patients with CM receiving GMB versus PBO attained greater cost savings, although not statistically significant, through reduced lost productivity at work/school.

Migraine causes missed time or reduced productivity at home and work, which further imposes an economic burden on patients, referred to as indirect costs. In this study, we evaluated the indirect cost savings in patients with episodic or chronic migraine taking either galcanezumab or placebo for treatment. We collected data using a questionnaire called the Migraine Disability Assessment (MIDAS) that was completed by patients enrolled in three clinical studies in the United States (US), namely EVOLVE-1, EVOVLE-2 (episodic migraine patients), and REGAIN (chronic migraine patients). The MIDAS questionnaire evaluated time lost/reduced productivity at work/school, household work, and leisure activity in patients with episodic or chronic migraine. Using scores of the MIDAS questionnaire and standard annual wages for the US population, we calculated indirect costs in patients. A total of 805 patients with episodic migraine and 423 patients with chronic migraine were included in this study. In galcanezumab-treated patients with episodic migraine, a significant indirect cost saving was observed through decrease in time lost/reduced productivity at work/school, household work, and leisure activity compared with patients who received placebo. In galcanezumab-treated patients with chronic migraine, indirect cost saving observed through decrease in time lost/reduced productivity at work/school were not statistically different from placebo-treated patients. The relatively lower cost savings observed in patients with chronic migraine may be due to greater disease burden compared to patients with episodic migraine. Results of this study suggest that patients with migraine receiving galcanezumab may obtain indirect cost savings.

Annual indirect cost savings in patients with episodic or chronic migraine: post-hoc analyses from multiple galcanezumab clinical trials.

AIM: This post-hoc analysis estimated annual indirect cost savings with galcanezumab (GMB) treatment in patients with episodic migraine (EM) or chronic migraine (CM). METHODS: Data from 4 randomized, Phase 3, double-blind (DB), placebo (PBO)-controlled studies of GMB were analyzed: EVOLVE-1 and EVOLVE-2 (EM, 6-months DB), REGAIN (CM, 3-months DB), and CONQUER (previous failure of 2-4 migraine preventive medication categories, 3-months DB). Indirect costs were calculated at baseline and Month 3 using the first 2 items in Migraine Disability Assessment (MIDAS): (A + B)/60*country specific annual wage (A = days of missed work/school; B = days of reduced productivity at work/school; assuming 60 working days in 3 months). All costs were annualized and expressed in international dollars (Int$) in 2018. ANCOVA models estimated the indirect cost savings as a change from baseline. Secondary analyses determined cost savings by employment and responder status. RESULTS: Patients (>80% females) from EVOLVE-1 and -2 (n = 1,201; mean age 41.9 years), REGAIN (n = 759; mean age 41.3 years), and CONQUER (n = 453; mean age ∼46.0 years) were analyzed. GMB showed significant indirect cost savings for EM (Int$6256, p < .0001) and CM (Int$7129, p = .0002), with substantial savings for patients with previous failure of 2-4 migraine preventive medication categories (EM: Int$5664, p = .0030; CM: Int$5181, p = .1300). Compared with PBO, GMB showed significantly greater indirect cost savings for EM (p = .0156) and patients with previous failure of 2-4 migraine preventive medication categories (p = .0340). Employed patients with CM (p = .0018) and with previous failure of 2-4 migraine preventive medication categories (p < .0001) had significant cost savings after GMB treatment. GMB showed significant indirect cost savings in patients with a reduction in migraine headache days. CONCLUSION: GMB treatment resulted in annual indirect cost savings in patients with EM, CM, and with previous failure of 2-4 migraine preventive medication categories, with similar observations in the sensitivity analyses.

[IMMP2L gene mutation activates mitochondrial apoptotic pathway to aggravate cerebral ischemic injury in mice].

Objective To investigate the effect of inner mitochondrial membrane peptidase 2-like (IMMP2L) gene mutation on cerebral ischemic injury and its mechanism. Methods The cerebral ischemia/reperfusion (I/R) model was established in wild-type (WT) mice and mice with IMMP2L gene mutation (IMMP2L+/-) by middle cerebral artery occlusion (MCAO), and cortical tissues were collected at 0, 1, 5 and 24 hours after reperfusion. Laser speckle contrast imaging (LSCI) was used to monitor the change in cerebral blood flow (CBF). Longa behavioral score was used to evaluate neurological function. triphenyltetrazolium chloride (TTC), HE staining was used to evaluate cerebral infarction and neuron injury, TUNEL was used to evaluate the neuronal apoptosis. The protein expression of cleaved caspase-3 and apoptosis-inducing factor (AIF)was analyzed by Western blotting. The changes of cerebral blood flow (CBF) were monitored by laser speckle contrast imaging (LSCI), neurological function was evaluated by longa behavioral score, and cerebral infarction area and neuronal injury were observed by TTC staining and HE staining respectively; the changes of neuronal apoptosis were analyzed by TUNEL, and the protein expressions of cleaved caspase-3 (c-caspase-3) and apoptosis inducing factor (AIF) were detected by Western blotting. Results The neurobehavioral score was significantly higher in the IMMP2L+/- versus WT mice. The volume of the infarcted region, the number of degenerated neurons, and the degree of cerebral edema all increased at 5 and 24 hours after reperfusion. The apoptotic neurons increased at 0, 1, 5 and 24 hours after reperfusion and the protein levels of c-caspase-3 and AIF were up-regulated at 5 and 24 hours after I/R. Conclusion IMMP2L mutation aggravates cerebral ischemic injury by activating the mitochondrial apoptosis pathway.

Patient-Perceived Versus Actual Risk of Cardiovascular Disease and Associated Willingness to Consider and Use Prevention Therapy.

BACKGROUND: Cardiovascular prevention guidelines use estimated 10-year atherosclerotic cardiovascular disease (CVD) risk based on the pooled cohort equations to guide treatment decisions and engage patients in shared decision-making. We sought to determine patient perceived versus actual risk of atherosclerotic CVD and associations with willingness for preventive therapy. METHODS: We evaluated calculated and perceived CVD risk among 4187 patients across 124 sites in the Patient and Provider Assessment of Lipid Management Registry. Ten-year risk was assessed using the pooled cohort equations; risk relative-to-peers was determined based on age-, sex-, and race-based percentiles; and patient estimates of risk were assessed using patient surveys. Poisson regression models evaluated associations between risk estimates, statin use, and willingness to take prevention therapy. RESULTS: Overall, there was no correlation between patients' estimates of their 10-year CVD risk and calculated 10-year risk (ρ=-0.01, Pcorrelation=0.46), regardless of age, sex, race, or socioeconomic status. The majority (72.2%) overestimated their 10-year CVD risk relative to the pooled cohorts equation (mean perceived 33.3% versus mean calculated 17.1%, Pdifference<0.01). Patients' perceptions of their risk relative-to-peers were slightly correlated with standardized risk percentiles (ρ=0.19, P<0.01), although most had overly optimistic views of how risk compared with their peers. Increasing perceived risk was not associated with current statin use (P=0.18) but was associated with willingness to consider future prevention therapy (P<0.01). Perceived risk relative-to-peers was associated with increased prevalent statin use (risk ratio 1.04 per category increase [95% CI, 1.02-1.06]) and reported willingness for prevention therapy (risk ratio 1.11 [95% CI, 1.07-1.16]). CONCLUSIONS: When asked, most patients overestimate their 10-year risk but hold an optimistic bias of their risk relative to age-, race-, and sex-matched peers. Providing accurate absolute risk assessments to patients without proper context may paradoxically decrease many patients' perceived risk of CVD, thereby disincentivizing initiation of CVD risk reduction therapy.

Antiplatelet patterns and outcomes in patients with atrial fibrillation not prescribed an anticoagulant after stroke.

BACKGROUND: To determine association of discharge antiplatelet therapy prescription with 1-year outcomes among patients with AF admitted with acute ischemic stroke and discharged without oral anticoagulation. METHODS: In a retrospective cohort study from the Get With The Guidelines-Stroke registry, we identified all Medicare fee-for-service beneficiaries 65 years or older with AF or atrial flutter admitted with acute ischemic stroke and discharged without oral anticoagulation from April 2003 through December 2014, and we determined association of discharge antiplatelet therapy prescription with 1-year outcomes using Medicare claims data. Primary outcomes were 1-year mortality and composite endpoint of major adverse cardiovascular/neurologic/bleeding events (MACNBE). RESULTS: Of 64,228 subjects (median [interquartile range] age, 84 [78-89] years; 62.5% female), 54,621 (85.0%) were discharged with antiplatelet therapy, and 9607 (15.0%) were discharged with no antithrombotic therapy. The unadjusted rates of 1-year mortality were lower among patients receiving antiplatelet therapy (37.3%) than among those receiving no antithrombotic therapy (48.1%); unadjusted rates of MACNBE were lower for those receiving antiplatelet therapy (45.5%) compared with those receiving no antithrombotic therapy (55.2%). After adjusting for potential confounders, antiplatelet therapy prescription was associated with reduced 1-year mortality (adjusted hazard ratio [HR] 0.64, 95% confidence interval [CI] 0.62-0.66, P < .001) and MACNBE (adjusted HR 0.69, 95% CI 0.67-0.71, P < .001). CONCLUSIONS: Among Medicare beneficiaries with AF admitted for acute ischemic stroke but not discharged on oral anticoagulant therapy, antiplatelet therapy, compared with no antithrombotic therapy, was associated with reduced 1-year mortality and MACNBE.

Target Doses of Heart Failure Medical Therapy and Blood Pressure: Insights From the CHAMP-HF Registry.

OBJECTIVES: This study sought to determine the rate of use of target doses of foundational guideline-directed medical therapy (GDMT) in a contemporary cohort of patients with heart failure with reduced ejection fraction (HFrEF) across systolic blood pressure (SBP) categories. BACKGROUND: Patients with HFrEF are infrequently titrated to recommended doses of GDMT. The relationship between SBP and achieving GDMT target doses is not well studied. METHODS: Patients enrolled in the CHAMP-HF (Change the Management of Patients With Heart Failure) registry without documented intolerance to angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), angiotensin receptor-neprilysin inhibitors (ARNIs), and beta blockers (BBs) were assessed at enrollment. We estimated the proportion receiving target doses (% of target dose [95% confidence interval (CI)]) based on the most recent American College of Cardiology/American Heart Association/Heart Failure Society of America heart failure guidelines at baseline in all patients, and by SBP category (≥110 vs. <110 mm Hg). RESULTS: Of the 3,095 patients eligible for analysis, 2,421 (78.2%) had SBP ≥110 mm Hg. The proportion of patients receiving target doses were 18.7% (95% CI: 17.3% to 20.0%; BB), 10.8% (95% CI: 9.7% to 11.9%; ACEI/ARB), and 2.0% (95% CI: 1.5% to 2.5%; ARNI). Among those with SBP <110 mm Hg (n = 674), 17.5% (95% CI: 14.6% to 20.4%; BB), 6.2% (95% CI: 4.4% to 8.1%; ACEI/ARB), and 1.8% (95% CI: 0.8% to 2.8%; ARNI) were receiving target doses. Among those with SBP ≥110 mm Hg (n = 2,421), 19.0% (95% CI: 17.4% to 20.6%; BB), 12.1% (95% CI: 10.8% to 13.4%; ACEI/ARB), and 2.0% (95% CI: 1.5% to 2.6%; ARNI) were receiving target doses. CONCLUSIONS: In a large, contemporary registry of outpatients with chronic HFrEF eligible for treatment with BBs and ACEI/ARB/ARNI, <20% of patients were receiving target doses, even among those with SBP ≥110 mm Hg.

Influence of Cardiovascular Risk Communication Tools and Presentation Formats on Patient Perceptions and Preferences.

Importance: Practice guidelines recommend that clinicians engage patients in treatment decisions and explain atherosclerotic cardiovascular disease (ASCVD) risk but do not describe how to communicate this risk most effectively. Objective: To determine how the ASCVD risk time horizon, outcome, and presentation format influence risk perceptions and treatment preferences. Design, Setting, and Participants: From May 27, 2015, through November 12, 2015, participants from the Patient and Provider Assessment of Lipid Management Registry at 140 US cardiology, primary care, and endocrinology practices were presented 3 independent scenarios (representing the same hypothetical patient) and asked to rate their perceived risk and willingness to take medication to lower risk in light of (1) a 15% 10-year ASCVD event risk, (2) a 4% 10-year cardiovascular disease (CVD) death risk, and (3) a 50% lifetime ASCVD event risk. Exposures: Participants were randomized to receive risk estimates using numbers only, a bar graph, or a face pictogram. Results: Of 3566 eligible participants, 2708 (76.9%) responded (median age, 67 years [interquartile range, 61-76 years]; 280 [10.3%] African American; 1491 men [55.1%]). When shown the lifetime ASCVD risk, respondents were more likely to consider the risk "high to very high" than when presented the 10-year ASCVD risk or the CVD death risk (70.1% vs 31.4% vs 25.7%, respectively; both P < .001). Treatment willingness was also the highest for lifetime ASCVD risk (77.9% very willing) followed by 10-year ASCVD risk (68.1%) and 10-year CVD death risk (63.1%; both P < .001). Compared with participants who were shown a bar graph or no graphic, those who were shown the risk information with a pictogram had the lowest perception of disease severity and the lowest willingness to consider therapy. These findings were robust across demographic and socioeconomic subgroups. Conclusions and Relevance: The format, time horizon, and outcome used for risk estimation influence patient perceptions and should be considered when designing risk communication tools. When shown lifetime risk estimates, patients had higher risk perception and willingness for therapy than when shown 10-year estimates. Pictogram risk displays may decrease risk perception and consideration for treatment.

Medical Therapy for Heart Failure With Reduced Ejection Fraction: The CHAMP-HF Registry.

BACKGROUND: Guidelines strongly recommend patients with heart failure with reduced ejection fraction (HFrEF) be treated with multiple medications proven to improve clinical outcomes, as tolerated. The degree to which gaps in medication use and dosing persist in contemporary outpatient practice is unclear. OBJECTIVES: This study sought to characterize patterns and factors associated with use and dose of HFrEF medications in current practice. METHODS: The CHAMP-HF (Change the Management of Patients with Heart Failure) registry included outpatients in the United States with chronic HFrEF receiving at least 1 oral medication for management of HF. Patients were characterized by baseline use and dose of angiotensin-converting enzyme inhibitor (ACEI)/angiotensin II receptor blocker (ARB), angiotensin receptor neprilysin inhibitor (ARNI), beta-blocker, and mineralocorticoid receptor antagonist (MRA). Patient-level factors associated with medication use were examined. RESULTS: Overall, 3,518 patients from 150 primary care and cardiology practices were included. Mean age was 66 ± 13 years, 29% were female, and mean EF was 29 ± 8%. Among eligible patients, 27%, 33%, and 67% were not prescribed ACEI/ARB/ARNI, beta-blocker, and MRA therapy, respectively. When medications were prescribed, few patients were receiving target doses of ACEI/ARB (17%), ARNI (14%), and beta-blocker (28%), whereas most patients were receiving target doses of MRA therapy (77%). Among patients eligible for all classes of medication, 1% were simultaneously receiving target doses of ACE/ARB/ARNI, beta-blocker, and MRA. In adjusted models, older age, lower blood pressure, more severe functional class, renal insufficiency, and recent HF hospitalization generally favored lower medication utilization or dose. Social and economic characteristics were not independently associated with medication use or dose. CONCLUSIONS: In this contemporary outpatient HFrEF registry, significant gaps in use and dose of guideline-directed medical therapy remain. Multiple clinical factors were associated with medication use and dose prescribed. Strategies to improve guideline-directed use of HFrEF medications remain urgently needed, and these findings may inform targeted approaches to optimize outpatient medical therapy.

Characteristics and Treatments of Patients Enrolled in the CHAMP-HF Registry Compared With Patients Enrolled in the PARADIGM-HF Trial.

BACKGROUND: The US Food and Drug Administration approved sacubitril/valsartan for patients with chronic heart failure (HF) with reduced ejection fraction in 2015 on the basis of the results of the PARADIGM-HF (Prospective Comparison of ARNI [Angiotensin Receptor Neprilysin Inhibitor] With ACEI [Angiotensin-Converting Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial. There are limited data assessing the generalizability of PARADIGM-HF trial participants to a broader population of patients with HF with reduced ejection fraction routinely encountered in outpatient clinical practice. METHODS AND RESULTS: We compared the baseline characteristics of patients in the PARADIGM-HF trial with those in the CHAMP-HF (Change the Management of Patients With Heart Failure) study a large US outpatient registry of patients with HF with reduced ejection fraction. Patients in the PARADIGM-HF trial (n=8442) were similar to those in the CHAMP-HF registry (n=3497) in terms of age (mean, 64 versus 66 years), sex (22% versus 29% women), New York Heart Association class III to IV (25% versus 32%), systolic blood pressure (mean, 121 versus 121 mm Hg), left ventricular ejection fraction (mean, 29% versus 29%), and other key baseline characteristics. The median (25th-75th percentile) Meta-Analysis Global Group in Chronic Heart Failure risk scores were similar for the 2 studies (20 [16-24] versus 22 [8-27]). Despite this, only 13% of patients in the CHAMP-HF registry were prescribed sacubitril/valsartan at baseline. CONCLUSIONS: These data suggest participants randomized in the PARADIGM-HF trial have similar baseline characteristics to those encountered in routine outpatient clinical practice, but there is a substantial lag in the adoption of sacubitril/valsartan for patients with chronic HF with reduced ejection fraction.

Health Status Disparities by Sex, Race/Ethnicity, and Socioeconomic Status in Outpatients With Heart Failure.

OBJECTIVES: This study sought to describe the health status of outpatients with heart failure and reduced ejection fraction (HFrEF) by sex, race/ethnicity, and socioeconomic status (SES). BACKGROUND: Although a primary goal in treating patients with HFrEF is to optimize health status, whether disparities by sex, race/ethnicity, and SES exist is unknown. METHODS: In the CHAMP-HF (Change the Management of Patients with Heart Failure) registry, the associations among sex, race, and SES and health status, as measured by the Kansas City Cardiomyopathy Questionnaire-overall summary (KCCQ-os) score (range 0 to 100; higher scores indicate better health status) was compared among 3,494 patients from 140 U.S. clinics. SES was categorized by total household income. Hierarchical multivariate linear regression estimated differences in KCCQ-os score after adjusting for 31 patient characteristics and 10 medications. RESULTS: Overall mean KCCQ-os scores were 64.2 ± 24.0 but lower for women (29% of sample; 60.3 ± 24.0 vs. 65.9 ± 24.0, respectively; p < 0.001), for blacks (60.5 ± 25.0 vs. 64.9 ± 23.0, respectively; p < 0.001), for Hispanics (59.1 ± 21.0 vs. 64.9 ± 23.0, respectively; p < 0.001), and for those with the lowest income (<$25,000; mean: 57.1 vs. 63.1 to 74.7 for other income categories; p < 0.001). Fully adjusted KCCQ-os scores were 2.2 points lower for women (95% confidence interval [CI]: -3.8 to -0.6; p = 0.007), no different for blacks (p = 0.74), 4.0 points lower for Hispanics (95% CI: -6.6 to -1.3; p = 0.003), and lowest in the poorest patients (4.7 points lower than those with the highest income (95% CI: 0.1 to 9.2; p = 0.045; p for trend = 0.003). CONCLUSIONS: Among outpatients with HFrEF, women, blacks, Hispanics, and poorer patients had worse health status, which remained significant for women, Hispanics, and poorer patients in fully adjusted analyses. This suggests an opportunity to further optimize treatment to reduce these observed disparities.

Statin Use and Adverse Effects Among Adults >75 Years of Age: Insights From the Patient and Provider Assessment of Lipid Management (PALM) Registry.

BACKGROUND: Current statin use and symptoms among older adults in routine community practice have not been well characterized since the release of the 2013 American College of Cardiology/American Heart Association guideline. METHODS AND RESULTS: We compared statin use and dosing between adults >75 and ≤75 years old who were eligible for primary or secondary prevention statin use without considering guideline-recommended age criteria. The patients were treated at 138 US practices in the Patient and Provider Assessment of Lipid Management (PALM) registry in 2015. Patient surveys also evaluated reported symptoms while taking statins. Multivariable logistic regression models examined the association between older age and statin use and dosing. Among 6717 people enrolled, 1704 (25%) were >75 years old. For primary prevention, use of any statin or high-dose statin did not vary by age group: any statin, 62.6% in those >75 years old versus 63.1% in those ≤75 years old (P=0.83); high-dose statin, 10.2% versus 12.3% in the same groups (P=0.14). For secondary prevention, older patients were slightly less likely to receive any statin (80.1% versus 84.2% [P=0.003]; adjusted odds ratio, 0.81; 95% confidence interval, 0.66-1.01 [P=0.06]), but were much less likely to receive a high-intensity statin (23.5% versus 36.2% [P<0.0001]; adjusted odds ratio, 0.54; 95% confidence interval, 0.45-0.65 [P=0.0001]). Among current statin users, older patients were slightly less likely to report any symptoms (41.3% versus 46.6%; P=0.003) or myalgias (27.3% versus 33.3%; P<0.001). CONCLUSIONS: Overall use of statins was similar for primary prevention in those aged >75 years versus younger patients, yet older patients were less likely to receive high-intensity statins for secondary prevention. Statins appear to be similarly tolerated in older and younger adults.

Health Status Variation Across Practices in Outpatients With Heart Failure: Insights From the CHAMP-HF (Change the Management of Patients With Heart Failure) Registry.

BACKGROUND: Although a key treatment goal for patients with heart failure with reduced ejection fraction is to optimize their health status (their symptoms, function, and quality of life), the variability across outpatient practices in achieving this goal is unknown. METHODS AND RESULTS: In the CHAMP-HF (Change the Management of Patients With Heart Failure) registry, associations between baseline practice characteristics and Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary (OS) and Symptom Frequency (SF) scores were assessed in 3494 patients across 140 US practices using hierarchical regression after accounting for 23 patient and 11 treatment characteristics. We then calculated an adjusted median odds ratio to quantify the average difference in likelihood that a patient would have excellent (KCCQ-OS, ≥75) health status or minimal (monthly or fewer) symptoms (KCCQ-SF, ≥75) when treated at one practice versus another, at random. The mean (±SD) KCCQ-OS and KCCQ-SF were 64.2±24 and 68.9±25.6, with 40% (n=1380) and 50% (n=1760) having KCCQ scores ≥75, respectively. The adjusted median odds ratio across practices, for KCCQ-OS ≥75, was 1.70 (95% confidence interval, 1.54-1.99; P<0.001) indicating a median 70% higher odds of a patient having good-to-excellent health status when treated at one random practice versus another. In regard to KCCQ-SF, the adjusted median odds ratio for KCCQ-SF ≥75 was 1.54 (95% confidence interval, 1.41-1.76; P=0.001). CONCLUSIONS: In a large, contemporary registry of outpatients with chronic heart failure with reduced ejection fraction, we observed significant practice-level variability in patients' health status. Quantifying patients' health status as a measure of quality should be explored as a foundation for improving care. CLINICAL TRIAL REGISTRATION: URL: https://www.centerwatch.com. Unique identifier: TX144901.

Overtreatment and Deintensification of Diabetic Therapy among Medicare Beneficiaries.

BACKGROUND: Deintensification of diabetic therapy is often clinically appropriate for older adults, because the benefit of aggressive diabetes treatment declines with age, while the risks increase. OBJECTIVE: We examined rates of overtreatment and deintensification of therapy for older adults with diabetes, and whether these rates differed by medical, demographic, and socioeconomic characteristics. DESIGN, SUBJECTS, AND MAIN MEASURES: We analyzed Medicare claims data from 10 states, linked to outpatient laboratory values to identify patients potentially overtreated for diabetes (HbA1c < 6.5% with fills for any diabetes medications beyond metformin, 1/1/2011-6/30/2011). We examined characteristics associated with deintensification for potentially overtreated diabetic patients. We used multinomial logistic regression to examine whether patient characteristics associated with overtreatment of diabetes differed from those associated with undertreatment (i.e. HbA1c > 9.0%). KEY RESULTS: Of 78,792 Medicare recipients with diabetes, 8560 (10.9%) were potentially overtreated. Overtreatment of diabetes was more common among those who were over 75 years of age and enrolled in Medicaid (p < 0.001), and was less common among Hispanics (p = 0.009). Therapy was deintensified for 14% of overtreated diabetics. Appropriate deintensification of diabetic therapy was more common for patients with six or more chronic conditions, more outpatient visits, or living in urban areas; deintensification was less common for those over age 75. Only 6.9% of Medicare recipients with diabetes were potentially undertreated. Variables associated with overtreatment of diabetes differed from those associated with undertreatment. CONCLUSIONS: Medicare recipients are more frequently overtreated than undertreated for diabetes. Medicare recipients who are overtreated for diabetes rarely have their regimens deintensified.

Outcomes Associated With Extraction Versus Capping and Abandoning Pacing and Defibrillator Leads.

BACKGROUND: Lead management is an increasingly important aspect of care in patients with cardiac implantable electronic devices; however, relatively little is known about long-term outcomes after capping and abandoning leads. METHODS: Using the 5% Medicare sample, we identified patients with de novo cardiac implantable electronic device implantations between January 1, 2000, and December 31, 2013, and with a subsequent lead addition or extraction ≥12 months after the de novo implantation. Patients who underwent extraction for infection were excluded. Using multivariable Cox proportional hazards models, we compared cumulative incidence of all-cause mortality, device-related infection, device revision, and lead extraction at 1 and 5 years for the extraction versus the cap and abandon group. RESULTS: Among 6859 patients, 1113 (16.2%) underwent extraction, whereas 5746 (83.8%) underwent capping and abandonment. Extraction patients tended to be younger (median, 78 versus 79 years; P<0.0001), were less likely to be male (65% versus 68%; P=0.05), and had shorter lead dwell time (median, 3.0 versus 4.0 years; P<0.0001) and fewer comorbidities. Over a median follow-up of 2.4 years (25th, 75th percentiles, 1.0, 4.3 years), the overall 1-year and 5-year cumulative incidence of mortality was 13.5% (95% confidence interval [CI], 12.7-14.4) and 54.3% (95% CI, 52.8-55.8), respectively. Extraction was associated with a lower risk of device infection at 5 years relative to capping (adjusted hazard ratio, 0.78; 95% CI, 0.62-0.97; P=0.027). There was no association between extraction and mortality, lead revision, or lead extraction at 5 years. CONCLUSIONS: Elective lead extraction for noninfectious indications had similar long-term survival to that for capping and abandoning leads in a Medicare population. However, extraction was associated with lower risk of device infections at 5 years.

The Effect of Clinical Care Location on Clinical Outcomes After Peripheral Vascular Intervention in Medicare Beneficiaries.

OBJECTIVES: Modifications in reimbursement rates by Medicare in 2008 have led to peripheral vascular interventions (PVI) being performed more commonly in outpatient and office-based clinics. The objective of this study was to determine the effects of this shift in clinical care setting on clinical outcomes after PVI. BACKGROUND: Modifications in reimbursement have led to peripheral vascular intervention (PVI) being more commonly performed in outpatient hospital settings and office-based clinics. METHODS: Using a 100% national sample of Medicare beneficiaries from 2010 to 2012, we examined 30-day and 1-year rates of all-cause mortality, major lower extremity amputation, repeat revascularization, and all-cause hospitalization by clinical care location of index PVI. RESULTS: A total of 218,858 Medicare beneficiaries underwent an index PVI between 2010 and 2012. Index PVIs performed in inpatient settings were associated with higher 1-year rates of all-cause mortality (23.6% vs. 10.4% and 11.7%; p < 0.001), major lower extremity amputation (10.1% vs. 3.7% and 3.5%; p < 0.001), and all-cause repeat hospitalization (63.3% vs. 48.5% and 48.0%; p < 0.001), but lower rates of repeat revascularization (25.1% vs. 26.9% vs. 38.6%; p < 0.001) when compared with outpatient hospital settings and office-based clinics, respectively. After adjustment for potential confounders, patients treated in office-based clinics remained more likely than patients in inpatient hospital settings to require repeat revascularization within 1 year across all specialties. There was also a statistically significant interaction effect between location of index revascularization and geographic region on the occurrence of all-cause hospitalization, repeat revascularization, and lower extremity amputation. CONCLUSIONS: Index PVI performed in office-based settings was associated with a higher hazard of repeat revascularization when compared with other settings. Differences in clinical outcomes across treatment settings and geographic regions suggest that inconsistent application of PVI may exist and highlights the need for studies to determine optimal delivery of PVI in clinical practice.

Change the management of patients with heart failure: Rationale and design of the CHAMP-HF registry.

Heart failure (HF) with reduced ejection fraction (HFrEF) is a common and costly condition that diminishes patients' health status and confers a poor prognosis. Despite the availability of multiple guideline-recommended pharmacologic and cardiac device therapies for patients with chronic HFrEF, outcomes remain suboptimal. Currently, there is limited insight into the rationale underlying clinical decisions by health care providers and patient factors that guide the use and intensity of outpatient HF treatments. A better understanding of current practice patterns has the potential to improve patients' outcomes. The CHAnge the Management of Patients with Heart Failure (CHAMP-HF) registry will evaluate the care and outcomes of patients with chronic HFrEF by assessing real-world treatment patterns, as well as the reasons for and barriers to medication treatment changes. CHAMP-HF will enroll approximately 5,000 patients with chronic HFrEF (left ventricular ejection fraction ≤40%) at approximately 150 US sites, and patients will be followed for a maximum duration of 24 months. Participating sites will collect data from both providers (HF history, examination findings, results of diagnostic studies, pharmacotherapy treatment patterns, decision-making factors, and clinical outcomes) and patients (medication adherence and patient-reported outcomes). The CHAMP-HF registry will provide a unique opportunity to study practice patterns and the adoption of new HF therapies across a diverse mix of health care providers and outpatient practices in the United States that care for HFrEF patients.