Absolute and Functional Iron Deficiency in the US, 2017-2020.

Importance: The prevalence of absolute and functional iron deficiency among adults in the US is unknown. Objective: To estimate the prevalence of absolute and iron deficiency and iron supplement use in the US across age, sex, and comorbidity categories. Design, Setting, and Participants: This cross-sectional study analyzed data from the National Health and Nutritional Examination Survey (NHANES) 2017 to 2020 prepandemic cycle. Participants included noninstitutionalized, civilian women and men aged 18 years or older who had available serum ferritin, iron, and unsaturated iron binding capacity measurements. Data analysis was performed from March 21, 2023, to July 5, 2024. Exposure: Absolute iron deficiency and functional iron deficiency. Main Outcomes and Measures: Absolute iron deficiency was defined as serum ferritin less than 30 ng/mL regardless of transferrin saturation. Functional iron deficiency was defined as serum ferritin greater than or equal to 30 ng/mL with transferrin saturation less than 20%. The prevalence of absolute and functional iron deficiency was estimated among all adults in the US and separately among women and men according to age category (>18 years to <50 years, 50-65 years, and ≥65 years) using recommended sample weights and sampling design factors to provide estimates representative of the national, noninstitutionalized civilian population. The 95% CIs were calculated using the Korn-Graubard method. Results: A total of 8021 US adults (mean age, 48 years; 95% CI, 47-49 years; 52% [95% CI, 50%-53%] female) were included in this analysis. An estimated 14% (95% CI, 13%-15%) of adults in the US met the criteria for absolute iron deficiency, and an estimated 15% (95% CI, 14%-17%) met the criteria for functional iron deficiency. Among US adults without anemia, heart failure, chronic kidney disease, or current pregnancy, the estimated prevalence of absolute iron deficiency was 11% (95% CI, 10%-11%), and that of functional iron deficiency was 15% (95% CI, 14%-17%). The prevalence of functional iron deficiency exceeded that of absolute iron deficiency in all US adults except women younger than 50 years. Iron supplement use ranged from 22% (95% CI, 12%-37%) to 35% (95% CI, 29%-42%) of women with iron deficiency and 12% (95% CI, 5%-21%) to 18% (95% CI, 8%-32%) of men with iron deficiency depending on age. Conclusions and Relevance: These findings suggest that absolute and functional iron deficiency affect a large proportion of American adults even in the absence of anemia, heart failure, or chronic kidney disease. Further research on the role of functional iron deficiency in adverse health outcomes and on iron deficiency screening strategies is needed.

Drug-Drug Interactions and the Clinical Tolerability of Colchicine Among Patients With COVID-19: A Secondary Analysis of the COLCORONA Randomized Clinical Trial.

Importance: Colchicine has many drug-drug interactions with commonly prescribed medications. Only pharmacokinetic studies have provided data on colchicine drug-drug interactions. Objective: To evaluate the clinical tolerability of colchicine according to the presence or absence of a drug-drug interaction. Design, Setting, and Participants: A secondary analysis of the COLCORONA trial was performed. The COLCORONA trial was a randomized, double-blind, placebo-controlled trial conducted in Brazil, Canada, Greece, South Africa, Spain, and the US between March 23, 2020, and January 20, 2021. The COLCORONA trial included ambulatory patients with COVID-19 with at least 1 high-risk characteristic and compared the effects of colchicine (0.5 mg twice daily for 3 days, then 0.5 mg daily thereafter) with placebo for 27 days. Data analysis was performed from February 24, 2023, to June 20, 2024. Exposure: In this secondary analysis, baseline medications that had interactions with colchicine were identified using a previously published expert classification. Main Outcomes and Measures: The primary outcome for this analysis was the composite of serious and nonserious treatment-related and treatment-unrelated gastrointestinal adverse events. The secondary outcomes were other adverse events and the composite of death or hospital admission due to COVID-19 infection. Logistic regression models adjusted for age, sex, estimated glomerular filtration rate, diabetes, heart failure, and myocardial infarction were assessed for effect modification of the association between the randomization arm and the outcomes of interest by drug-drug interaction status. Results: The cohort included 2205 participants in the colchicine arm and 2227 in the placebo arm (median age, 54 [IQR, 47-61] years; 2389 [54%] women). The most common colchicine drug-drug interactions were rosuvastatin (12%) and atorvastatin (10%). In fully adjusted models, the odds of any gastrointestinal adverse event were 1.80 (95% CI, 1.51-2.15) times higher in the colchicine arm than the placebo arm among people without a drug-drug interaction and 1.68 (95% CI, 1.24-2.26) times higher in the colchicine arm than the placebo arm among people with a drug-drug interaction (P = .69 for interaction). Drug-drug interaction status did not significantly modify the effect of colchicine on the composite of COVID-19 hospitalization or death (odds ratio, 0.91; 95% CI, 0.59-1.40 for drug-drug interaction and 0.84; 95% CI, 0.60-1.19 for no drug-drug interaction; P = .80 for interaction). Conclusions and Relevance: In this secondary analysis of the COLCORONA trial, operational classification of drug interactions system class 3 or 4 drug-drug interactions did not appear to significantly increase the risk of colchicine-related adverse effects. Trial Registration: ClinicalTrials.gov Identifier: NCT04322682.

Anemia, Iron Deficiency, and Cause-Specific Mortality: The Atherosclerosis Risk in Communities Study.

INTRODUCTION: Anemia is a risk factor for all-cause mortality in older adults. Iron deficiency may also be associated with adverse outcomes, independent of its role in causing anemia. This study tested the hypotheses that anemia, and low ferritin among non-anemic participants, were associated with all-cause and cause-specific mortality in a community-based cohort of older adults. METHODS: Fasting blood was obtained from 5,070 ARIC participants (median age: 75 years) in 2011-2013. Anemia was defined by hemoglobin concentrations <12 g/dL in women and <13 g/dL in men. We classified 4,020 non-anemic participants by quartiles of plasma ferritin, measured by the SomaScan proteomics platform. Cox proportional hazards regression was used. Mortality was ascertained via phone calls with proxies as part of twice-yearly cohort follow-up, surveillance of local hospital discharge indexes, state death records, and linkage to the National Death Index. RESULTS: Of the total participants, 21% had anemia at baseline. Over a median of 7.5 years, there were 1,147 deaths, including 357 due to cardiovascular disease (CVD), 302 to cancer, and 132 to respiratory disease. Compared to those with normal hemoglobin, participants with anemia had a higher risk of all-cause mortality (hazard ratio 1.81 [95% CI: 1.60-2.06]), and mortality due to CVD (1.77 [1.41-2.22]), cancer (1.81 [1.41-2.33]), and respiratory disease (1.72 [1.18-2.52]) in demographics-adjusted models. In fully adjusted models, associations with all-cause mortality (1.37 [1.19-1.58]) and cause-specific mortality were attenuated. In non-anemic participants, lower ferritin levels were not associated with all-cause or cause-specific mortality, though associations were observed among participants with lesser evidence of inflammation (CRP below the median level of 1.9 mg/L) and for cancer mortality in men only. CONCLUSION: Anemia is common among older adults and is associated with all-cause mortality, as well as mortality due to CVD, cancer, and respiratory disease. Our results do not provide evidence that iron deficiency, independent of anemia, is associated with mortality in this population.

High Throughput Plasma Proteomics and Risk of Heart Failure and Frailty in Late Life.

Importance: Heart failure (HF) and frailty frequently coexist and may share a common pathobiology, although the underlying mechanisms remain unclear. Understanding these mechanisms may provide guidance for preventing and treating both conditions. Objective: To identify shared pathways between incident HF and frailty in late life using large-scale proteomics. Design, Setting, and Participants: In this cohort study, 4877 aptamers (Somascan v4) were measured among participants in the community-based longitudinal Atherosclerosis Risk In Communities (ARIC) cohort study at visit 3 (V3; 1993-1995; n = 10 638) and at visit 5 (V5; 2011-2013; n = 3908). Analyses were externally replicated among 3189 participants in the Cardiovascular Health Study (CHS). Data analysis was conducted from February 2022 to June 2023. Exposures: Protein aptamers, measured at study V3 and V5. Main Outcomes and Measures: Outcomes assessed included incident HF hospitalization after V3 and after V5, prevalent frailty at V5, and incident frailty between V5 and visit 6 (V6; 2016-2017; n = 4131). Frailty was assessed using the Fried criteria. Analyses were adjusted for age, gender, race, field center, hypertension, diabetes, smoking status, body mass index, estimated glomerular filtration rate, prevalent coronary heart disease, prevalent atrial fibrillation, and history of myocardial infarction. Mendelian randomization (MR) analysis was performed to assess potential causal effects of candidate proteins on HF and frailty. Results: A total of 4877 protein aptamers were measured among 10 638 participants at V3 (mean [SD] age, 60 [6] years; 4886 [46%] men). Overall, 286 proteins were associated with incident HF after V3 (822 events; P < 1.0 × 10-5), 83 of which were also associated with incident after V5 (336 events; P < 1.7 × 10-4). Among HF-free participants at V5 (n = 3908; mean [SD] age, 75 [5] years; 1861 [42%] men), 48 of 83 HF-associated proteins were associated with prevalent frailty (223 cases; P < 6.0 × 10-4), 18 of which were also associated with incident frailty at V6 (152 cases; P < 1.0 × 10-3). These proteins enriched fibrosis and inflammation pathways and demonstrated stronger associations with incident HF with preserved ejection fraction (HFpEF) than HF with reduced ejection fraction. All 18 proteins were associated with both prevalent frailty and incident HF in CHS. MR identified potential causal effects of several proteins on frailty and HF. Conclusions and Relevance: In this study, the proteins associated with risk of HF and frailty enrich for pathways related to inflammation and fibrosis as well as risk of HFpEF. Several of these proteins could potentially contribute to the shared pathophysiology of frailty and HF.

Trends in Oral Anticoagulant Use and Individual Expenditures Across the United States from 2014 to 2020.

BACKGROUND: Landmark clinical trials have expended the indications for the direct oral anticoagulants (DOACs), but contemporary data on usage and expenditure patterns are lacking. OBJECTIVE: This study aimed to assess annual trends in oral anticoagulant (OAC) utilization and expenditure across the United States (US) from 2014 to 2020. METHODS: We utilized the Medical Expenditure Panel Survey (MEPS) to study the trends of use and expenditures of warfarin, dabigatran, rivaroxaban, apixaban, and edoxaban between 2014 and 2020 in the US. Survey respondents reported OAC use within the past year, which was verified against pharmacy records. Payment information was obtained from the respondent's pharmacy and was categorized as third-party or self/out-of-pocket. Potential indications and medical conditions of interest for OAC therapy were identified from respondent-reported medical conditions. We estimated the national number of OAC users and total expenditures across age, sex, race, ethnicity, insurance, and medical condition subgroups. Trends of OAC users' characteristics, expenditure, and number of prescriptions were evaluated using the Mann-Kendall test for trends. RESULTS: Between 2014 and 2020, the number of warfarin users decreased from 3.8 million (70% of all OAC users) to 2.2 million (p = 0.007) [29% of all OAC users], while the number of DOAC users increased from 1.6 million (30% of all OAC users) to 5.4 million (p = 0.003) [70% of all OAC users]. The total expenditure of OACs in the US increased from $3.4 billion in 2014 to $17.8 billion in 2020 (p = 0.003), which was driven by the increase in DOAC expenditures (p = 0.003). CONCLUSIONS: DOACs have replaced warfarin as the preferred OAC in the US. The increased costs associated with DOAC use may decline when generic formulations are approved.

Colchicine's Role in Cardiovascular Disease Management.

Colchicine-an anti-inflammatory alkaloid-has assumed an important role in the management of cardiovascular inflammation ≈3500 years after its first medicinal use in ancient Egypt. Primarily used in high doses for the treatment of acute gout flares during the 20th century, research in the early 21st century demonstrated that low-dose colchicine effectively treats acute gout attacks, lowers the risk of recurrent pericarditis, and can add to secondary prevention of major adverse cardiovascular events. As the first Food and Drug Administration-approved targeted anti-inflammatory cardiovascular therapy, colchicine currently has a unique role in the management of atherosclerotic cardiovascular disease. The safe use of colchicine requires careful monitoring for drug-drug interactions, changes in kidney and liver function, and counseling regarding gastrointestinal upset. Future research should elucidate the mechanisms of anti-inflammatory effects of colchicine relevant to atherosclerosis, the potential role of colchicine in primary prevention, in other cardiometabolic conditions, colchicine's safety in cardiovascular patients, and opportunities for individualizing colchicine therapy using clinical and molecular diagnostics.

Management of direct oral anticoagulant drug interactions in hospitalized patients.

Moderate-strong CYP3A4 or Pgp inhibitors and inducers alter direct oral anticoagulant (DOAC) pharmacokinetics. Whether the presence of a DOAC drug-drug interaction (DDI) prompts in- hospital changes in management remains unknown. We identified all hospitalized patients at our institution who were admitted with a clinically relevant DOAC DDI from 01/2021 to 06/2021. Clinically relevant DOAC DDIs were defined as those listed in the prescribing information or FDA CYP3A4/Pgp inhibitors clinical indexes. We assessed the prevalence of DOAC DDIs and categorized their management as: drug stopped, drug held, or drug continued. For drugs that were continued we assessed whether the dose of the DOAC or interacting drug was increased, decreased or unchanged during the admission. We ascertained the number of DOAC DDIs that prompted an automated prescribing alert in our electronic health record (EHR). Finally, we conducted a logistic regression model to compare users of DOACs with DDI who had their regimen adjusted versus those without adjustments, focusing on outcomes of rehospitalization and death, adjusting for age and gender. Among 3,725 hospitalizations with a DOAC admission order, 197 (5%) had a clinically relevant DOAC DDI. The DOAC and the interacting drug were continued at discharge for 124 (63%) hospitalizations. The most frequent adjustments were stopping the interacting drug (73%) and stopping the DOAC (15%). Only 7 (4%) of DOAC DDIs prompted an EHR alert. The adjusted odds ratios for rehospitalizations and death, respectively, among patients whose regimens were adjusted compared to those whose were not, were 1.29 (95% CI, 0.67 to 2.48; P = 0.44) and 1.88 (95% CI, 0.91 to 3.89; P = 0.09). Clinically relevant DDIs with DOACs occur infrequently among hospitalized patients and usually are managed without stopping the DOAC. The clinical impact of such DDIs and subsequent adjustments on thrombotic and hemorrhagic outcomes requires further investigation.

Plasma Ferritin Levels, Incident Heart Failure, and Cardiac Structure and Function: The ARIC Study.

BACKGROUND: Whether iron deficiency contributes to incident heart failure (HF) and cardiac dysfunction has important implications given the prevalence of iron deficiency and the availability of several therapeutics for iron repletion. OBJECTIVES: The aim of this study was to estimate the associations of plasma ferritin level with incident HF overall, HF phenotypes, and cardiac structure and function measures in older adults. METHODS: Participants in the ongoing, longitudinal ARIC (Atherosclerosis Risk In Communities) study who were free of prevalent HF and anemia were studied. The associations of plasma ferritin levels with incident HF overall and heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF) were estimated using Cox proportional hazards regression models. Linear regression models estimated the cross-sectional associations of plasma ferritin with echocardiographic measures of cardiac structure and function. RESULTS: The cohort included 3,472 individuals with a mean age of 75 ± 5 years (56% women, 14% Black individuals). In fully adjusted models, lower ferritin was associated with higher risk for incident HF overall (HR: 1.20 [95% CI: 1.08-1.34] per 50% lower ferritin level) and higher risk for incident HFpEF (HR: 1.28 [95% CI: 1.09-1.50]). Associations with incident HFrEF were not statistically significant. Lower ferritin levels were associated with higher E/e' ratio and higher pulmonary artery systolic pressure after adjustment for demographics and HF risk factors but not with measures of left ventricular structure or systolic function. CONCLUSIONS: Among older adults without prevalent HF or anemia, lower plasma ferritin level is associated with a higher risk for incident HF, HFpEF, and higher measures of left ventricular filling pressure.

Large scale plasma proteomics identifies novel proteins and protein networks associated with heart failure development.

Heart failure (HF) causes substantial morbidity and mortality but its pathobiology is incompletely understood. The proteome is a promising intermediate phenotype for discovery of novel mechanisms. We measured 4877 plasma proteins in 13,900 HF-free individuals across three analysis sets with diverse age, geography, and HF ascertainment to identify circulating proteins and protein networks associated with HF development. Parallel analyses in Atherosclerosis Risk in Communities study participants in mid-life and late-life and in Trøndelag Health Study participants identified 37 proteins consistently associated with incident HF independent of traditional risk factors. Mendelian randomization supported causal effects of 10 on HF, HF risk factors, or left ventricular size and function, including matricellular (e.g. SPON1, MFAP4), senescence-associated (FSTL3, IGFBP7), and inflammatory (SVEP1, CCL15, ITIH3) proteins. Protein co-regulation network analyses identified 5 modules associated with HF risk, two of which were influenced by genetic variants that implicated trans hotspots within the VTN and CFH genes.

Large-Scale Proteomics Identifies Novel Biomarkers and Circulating Risk Factors for Aortic Stenosis.

BACKGROUND: Limited data exist regarding risk factors for aortic stenosis (AS). The plasma proteome is a promising phenotype for discovery of novel biomarkers and potentially causative mechanisms. OBJECTIVES: The aim of this study was to discover novel biomarkers with potentially causal associations with AS. METHODS: We measured 4,877 plasma proteins (SomaScan aptamer-affinity assay) among ARIC (Atherosclerosis Risk In Communities) study participants in mid-life (visit 3 [V3]; n = 11,430; age 60 ± 6 years) and in late-life (V5; n = 4,899; age 76 ± 5 years). We identified proteins cross-sectionally associated with aortic valve (AV) peak velocity (AVmax) and dimensionless index by echocardiography at V5 and with incident AV-related hospitalization after V3 with the use of multivariable linear and Cox proportional hazard regression. We assessed associations of candidate proteins with changes in AVmax over 6 years and with AV calcification with the use of cardiac computed tomography, replicated analysis in an independent sample, performed Mendelian randomization, and evaluated gene expression in explanted human AV tissue. RESULTS: Fifty-two proteins cross-sectionally were associated with AVmax and dimensionless index at V5 and with risk of incident AV-related hospitalization after V3. Among 3,413 participants in the Cardiovascular Health Study, 6 of those proteins were significantly associated with adjudicated moderate or severe AS, including matrix metalloproteinase 12 (MMP12), complement C1q tumor necrosis factor-related protein 1 (C1QTNF1), and growth differentiation factor-15. MMP12 was also associated with greater increase in AVmax over 6 years, greater degree of AV calcification, and greater expression in calcific compared with normal or fibrotic AV tissue. C1QTNF1 had consistent potential causal effects on both AS and AVmax according to Mendelian randomization analysis. CONCLUSIONS: These findings identify MMP12 as a potential novel circulating biomarker of AS risk and C1QTNF1 as a new putative target to prevent AS progression.

Targeting pharmacotherapies for inflammatory and cardiorenal endpoints in kidney disease.

ABSTRACT: Inflammation is an important contributor to excess cardiovascular risk and progressive renal injury in people with CKD. Dysregulation of the innate and adaptive immune system is accelerated by CKD and results in increased systemic inflammation, a heightened local vascular inflammatory response leading to accelerated atherosclerosis, and dysfunction of the cardiac and renal endothelium and microcirculation. Understanding and addressing the dysregulated immune system is a promising approach to modifying cardiorenal outcomes in people with CKD. However, targeted pharmacotherapies adopted from trials of non-CKD and cardio-rheumatology populations are only beginning to be developed and tested in human clinical trials. Pharmacotherapies that inhibit activation of the NLRP3 inflammasome and the downstream cytokines IL-1 and IL-6 are the most well-studied. However, most of the available evidence for efficacy is from small clinical trials with inflammatory and cardiorenal biomarker endpoints, rather than cardiovascular event endpoints, or from small CKD subgroups in larger clinical trials. Other pharmacotherapies that have proven beneficial for cardiorenal endpoints in people with CKD have been found to have pleiotropic anti-inflammatory benefits including statins, mineralocorticoid receptor antagonists, SGLT-2 inhibitors, and GLP-1 agonists. Finally, emerging therapies in CKD such as IL-6 inhibition, small-interfering RNA against lipoproteins, AhR inhibitors, and therapies adopted from the renal transplant population including mTOR inhibitors and T regulatory cell promoters may have benefits for cardiorenal and inflammatory endpoints but require further investigation in clinical trials.

MMP-2 Associates With Incident Heart Failure and Atrial Fibrillation: The ARIC Study.

BACKGROUND: MMP (matrix metalloproteinase)-2 participates in extracellular matrix regulation and may be involved in heart failure (HF), atrial fibrillation (AF), and coronary heart disease. METHODS: Among the 4693 ARIC study (Atherosclerosis Risk in Communities) participants (mean age, 75±5 years; 42% women) without prevalent HF, multivariable Cox proportional hazard models were used to estimate associations of plasma MMP-2 levels with incident HF, HF with preserved ejection fraction (≥50%), HF with reduced ejection fraction (<50%), AF, and coronary heart disease. Mediation of the association between MMP-2 and HF was assessed by censoring participants who developed AF or coronary heart disease before HF. Multivariable linear regression models were used to assess associations of MMP-2 with measures of left ventricular and left atrial structure and function. RESULTS: Compared with the 3 lower quartiles, the highest MMP-2 quartile associated with greater risk of incident HF overall (adjusted hazard ratio, 1.48 [95% CI, 1.21-1.81]), incident HF with preserved ejection fraction (1.44 [95% CI, 1.07-1.94]), incident heart failure with reduced ejection fraction (1.48 [95% CI, 1.08-2.02]), and incident AF (1.44 [95% CI, 1.18-1.77]) but not incident coronary heart disease (0.97 [95% CI, 0.71-1.34]). Censoring AF attenuated the MMP-2 association with HF with preserved ejection fraction. Higher plasma MMP-2 levels were associated with larger left ventricular end-diastolic volume index, greater left ventricular mass index, higher E/e' ratio, larger left atrial volume index, and worse left atrial reservoir and contractile strains (all P<0.001). CONCLUSIONS: Higher plasma MMP-2 levels associate with diastolic dysfunction, left atrial dysfunction, and a higher risk of incident HF and AF. AF is a mediator of MMP-2-associated HF with preserved ejection fraction risk.

Circulating neutrophil-related proteins associate with incident heart failure and cardiac dysfunction: The ARIC study.

AIMS: Neutrophil activity contributes to adverse cardiac remodelling in experimental acute cardiac injury and is modifiable with pharmacologic agents like colchicine. METHODS AND RESULTS: Neutrophil activity-related plasma proteins known to be affected by colchicine treatment were measured at Visit 3 (1993-1995) and Visit 5 (2011-2013) of the ARIC cohort study. A protein-based neutrophil activity score was derived from 10 candidate proteins using LASSO Cox regression. Associations with incident heart failure (HF) and with cardiac function using Cox proportional hazards regression and linear regression models, respectively. The mean ages at Visits 3 and 5 were 60 ± 6 and 75 ± 5 years, respectively, and 54% and 57% were women, respectively. Each 1-standard deviation increase in the neutrophil activity score was associated with a higher risk of incident HF in mid-life (hazard ratio [HR] 1.31, 95% confidence interval [CI] 1.25-1.37) and late-life (HR 1.23, 95% CI 1.14-1.34), with a higher HR for HF with preserved than reduced ejection fraction (HR 1.30, 95% CI 1.16-1.47 vs. HR 1.13, 95% CI 0.98-1.30). Higher neutrophil activity was associated with greater left ventricular end-diastolic volume index, mass index and diastolic and systolic dysfunction. CONCLUSIONS: Plasma proteins related to neutrophil function associate with incident HF in mid- and late-life and with adverse cardiac remodelling. Therapies that modify these proteins, such as colchicine, may represent promising targets for the prevention or treatment of HF.

Association of interleukin-6 and interleukin-18 with cardiovascular disease in older adults: Atherosclerosis Risk in Communities study.

AIMS: Interleukin-6 (IL-6) and interleukin-18 (IL-18), important cytokines implicated in atherosclerosis and inflammaging, were assessed for associations with global cardiovascular disease (CVD), atrial fibrillation (AF), and death in older adults. METHODS AND RESULTS: Participants from Atherosclerosis Risk in Communities study Visit 5 (mean age 75.4 ± 5.1 years) with IL-6 and IL-18 measurements were included (n = 5672). Cox regression models were used to assess associations of IL-6 and IL-18 with coronary heart disease (CHD), ischaemic stroke, heart failure (HF) hospitalization, global CVD (composite of CHD, stroke, and HF), AF, and all-cause death. Over a median follow-up of 7.2 years, there were 1235 global CVD events, 530 AF events, and 1173 deaths. Higher IL-6 [hazard ratio (HR) 1.57, 95% confidence interval (CI) 1.44-1.72 per log unit increase] and IL-18 (HR 1.13, 95% CI 1.01-1.26) were significantly associated with global CVD after adjustment for cardiovascular risk factors. Association between IL-6 and global CVD remained significant after further adjustment for high-sensitivity C-reactive protein (hs-CRP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and high-sensitivity troponin T (hs-TnT) but was no longer significant for IL-18 after further adjustments. Interleukin-6 was also associated with increased risk for CHD, HF, and AF after adjustment for covariates. Both IL-6 and IL-18 were associated with increased risk for all-cause death independent of cardiovascular risk factors and other biomarkers. CONCLUSION: Among older adults, both IL-6 and IL-18 were associated with global CVD and death. The association between IL-6 with CVD appears to be more robust and was independent of hs-CRP, NT-proBNP, and hs-TnT.

In older adults in the Atherosclerosis Risk in Communities study (average age 75 years), higher levels of interleukin-6 and interleukin-18, two proteins implicated in atherosclerosis and increased inflammation that occurs with ageing, significantly increased risk for global cardiovascular disease (including coronary heart disease, stroke, and heart failure) during the next ∼7 years; interleukin-6 also increased risk for global cardiovascular disease, coronary heart disease, heart failure, and atrial fibrillation even after adjustment for other biomarkers of inflammation and subclinical myocardial injury, and both interleukin-6 and interleukin-18 were associated with increased risk for all-cause death independent of cardiovascular risk factors and other biomarkers. In older adults, higher levels of interleukin-6 and interleukin-18 were both associated with increased risk for global cardiovascular disease (including coronary heart disease, stroke, and heart failure) and death.The association between interleukin-6 and global cardiovascular disease appeared to be stronger than that for interleukin-18 and remained significant after adjustment for other biomarkers of inflammation and subclinical myocardial injury.

Anticoagulation-Associated Adverse Drug Events in Hospitalized Patients Across Two Time Periods.

PURPOSE: Anticoagulants often cause adverse drug events (ADEs), comprised of medication errors and adverse drug reactions, in patients. Our study objective was to determine the clinical characteristics, types, severity, cause, and outcomes of anticoagulation-associated ADEs from 2015-2020 (a contemporary period following implementation of an electronic health record, infusion device technology, and anticoagulant dosing nomograms) and to compare them with those of a historical period (2004-2009). METHODS: We reviewed all anticoagulant-associated ADEs reported as part of our hospital-wide safety system. Reviewers classified type, severity, root cause, and outcomes for each ADE according to standard definitions. Reviewers also assessed events for patient harm. Patients were followed up to 30 days after the event. RESULTS: Despite implementation of enhanced patient safety technology and procedure, ADEs increased in the contemporary period. In the contemporary period, we found 925 patients who had 984 anticoagulation-associated ADEs, including 811 isolated medication errors (82.4%); 13 isolated adverse drug reactions (1.4%); and 160 combined medication errors, adverse drug reactions, or both (16.2%). Unfractionated heparin was the most frequent ADE-related anticoagulant (77.7%, contemporary period vs 58.3%, historical period). The most frequent anticoagulation-associated medication error in the contemporary period was wrong rate or frequency of administration (26.1%, n = 253), with the most frequent root cause being prescribing errors (21.3%, n = 207). The type, root cause, and harm from ADEs were similar between periods. CONCLUSIONS: We found that anticoagulation-associated ADEs occurred despite advances in patient safety technologies and practices. Events were common, suggesting marginal improvements in anticoagulant safety over time and ample opportunities for improvement.

Chronic Kidney Disease, Heart Failure, and Adverse Cardiac Remodeling in Older Adults: The ARIC Study.

BACKGROUND: The associations of kidney dysfunction and damage with heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF), as well as adverse cardiac remodeling, in late-life remain incompletely understood. OBJECTIVES: The authors sought to define the associations between kidney dysfunction and damage and incident HFrEF and HFpEF and cardiac structure and function in late-life. METHODS: This study included 5,170 adults initially free of a heart failure (HF) diagnosis who had estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR) measured at visit 5 (2011-2013) of the ARIC (Atherosclerosis Risk In Communities) study. Multivariable Cox proportional hazards models were used to estimate the associations of eGFR and UACR with incident HF, HFrEF, and HFpEF through 2019. Multivariable linear regression models were used to investigate the associations of eGFR and UACR at visit 5 with changes in cardiac structure and function between visits 5 and 7 in 2,313 participants with available echocardiograms. RESULTS: The mean age of participants was 76 ± 5 years, and 2,225 (43%) were men. The mean eGFR and median UACR were 66 ± 18 mL/min/1.73 m2 and 11 mg/g (25th, 75th percentile: 6, 22 mg/g), respectively. In fully adjusted models, both lower eGFR and higher UACR were associated with greater risk of any HF, HFrEF, and HFpEF. Lower eGFR was associated with larger increases in left ventricular end-diastolic volume index and worsening of diastolic measures. UACR did not associate with changes in cardiac structure or function. CONCLUSIONS: Mild to moderate kidney dysfunction and damage associate with incident HF and adverse cardiac remodeling in late-life.

Virtual Care Team Guided Management of Patients With Heart Failure During Hospitalization.

BACKGROUND: Scalable and safe approaches for heart failure guideline-directed medical therapy (GDMT) optimization are needed. OBJECTIVES: The authors assessed the safety and effectiveness of a virtual care team guided strategy on GDMT optimization in hospitalized patients with heart failure with reduced ejection fraction (HFrEF). METHODS: In a multicenter implementation trial, we allocated 252 hospital encounters in patients with left ventricular ejection fraction ≤40% to a virtual care team guided strategy (107 encounters among 83 patients) or usual care (145 encounters among 115 patients) across 3 centers in an integrated health system. In the virtual care team group, clinicians received up to 1 daily GDMT optimization suggestion from a physician-pharmacist team. The primary effectiveness outcome was in-hospital change in GDMT optimization score (+2 initiations, +1 dose up-titrations, -1 dose down-titrations, -2 discontinuations summed across classes). In-hospital safety outcomes were adjudicated by an independent clinical events committee. RESULTS: Among 252 encounters, the mean age was 69 ± 14 years, 85 (34%) were women, 35 (14%) were Black, and 43 (17%) were Hispanic. The virtual care team strategy significantly improved GDMT optimization scores vs usual care (adjusted difference: +1.2; 95% CI: 0.7-1.8; P < 0.001). New initiations (44% vs 23%; absolute difference: +21%; P = 0.001) and net intensifications (44% vs 24%; absolute difference: +20%; P = 0.002) during hospitalization were higher in the virtual care team group, translating to a number needed to intervene of 5 encounters. Overall, 23 (21%) in the virtual care team group and 40 (28%) in usual care experienced 1 or more adverse events (P = 0.30). Acute kidney injury, bradycardia, hypotension, hyperkalemia, and hospital length of stay were similar between groups. CONCLUSIONS: Among patients hospitalized with HFrEF, a virtual care team guided strategy for GDMT optimization was safe and improved GDMT across multiple hospitals in an integrated health system. Virtual teams represent a centralized and scalable approach to optimize GDMT.