Risk Of First Hospitalization Research Articles

Obesity, Cardiorenal Comorbidities, and Risk of Hospitalization in Patients With Heart Failure With Preserved Ejection Fraction

ObjectiveTo compare clinical features of patients with obesity-related heart failure (HF) with preserved ejection fraction (HFpEF) with those of patients with similar body mass index (BMI) but no HF and to examine the association between degree of obesity and risk for hospitalizations. MethodsThis was a retrospective analysis of 22,750 adults from a large US electronic health care data set (January 1, 2012, through July 31, 2019), including 4975 with HFpEF. Baseline characteristics were compared between patients with HFpEF and a control group matched on BMI, age, sex, and year of BMI record. Risk of first hospitalization was analyzed in the HFpEF sample with negative binomial and Cox proportional hazards models, adjusted for baseline comorbidities. ResultsCompared with controls without HF matched on BMI, age, sex, and year of BMI record, patients with HFpEF displayed worse kidney function, greater estimated plasma volume, and more cardiovascular comorbidities. Within the HFpEF cohort, patients with higher degree of obesity were younger and had fewer concomitant cardiovascular comorbidities than those with lower degree of obesity. The mean number of HF-related hospitalizations increased with higher degree of obesity (9.6 to 15.7/100 patient-years; P=.002), but higher degree of obesity was not associated with increased risk of non–HF-related hospitalizations. ConclusionAmong persons with obesity, increasing cardiorenal dysfunction and volume overload differentiate those with HFpEF. Among persons with established HFpEF, those with higher degree of obesity are younger and have fewer cardiovascular comorbidities but display a unique increased risk of HF-related hospitalizations, even as risk for other hospitalizations is not different.

Invited Perspective: Still Hazy? Air Pollution and Acute Kidney Injury.

Vol. 131, No. 4 Invited PerspectiveOpen AccessInvited Perspective: Still Hazy? Air Pollution and Acute Kidney Injuryis accompanied byAir Pollution and Acute Kidney Injury in the U.S. Medicare Population: A Longitudinal Cohort Study Simon Hsu, Jianzhao Bi, and Ian H. de Boer Simon Hsu Division of Nephrology and Kidney Research Institute, Department of Medicine, University of Washington, Seattle, Washington, USA Search for more papers by this author , Jianzhao Bi Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington, USA Search for more papers by this author , and Ian H. de Boer Address correspondence to Ian H. de Boer, 325 9th Ave., Box 359606, Seattle, WA 98104 USA. Telephone: (206) 616-5403. Email: E-mail Address: [email protected] https://orcid.org/0000-0003-1571-7592 Division of Nephrology and Kidney Research Institute, Department of Medicine, University of Washington, Seattle, Washington, USA Search for more papers by this author Published:10 April 2023CID: 041302https://doi.org/10.1289/EHP12860AboutSectionsPDF ToolsDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InReddit Air pollution poses prevailing and increasing threats to human health.1 Beyond its well-recognized role in respiratory and cardiovascular diseases, studies have now linked air pollution to numerous other illnesses, including chronic kidney disease (CKD).2 Defined as kidney damage or abnormal function persisting for at least 3 months,3 CKD afflicts greater than 800 million>800 million people worldwide and is most commonly detected by routine blood testing showing a decline in glomerular filtration rate (GFR) estimated from serum creatinine concentration (eGFR) or elevated urinary albumin excretion.4 Epidemiological evidence over the last few years has associated long-term exposure to air pollutants—including fine [less than or equal to 2.5 micrometers≤2.5μm in aerodynamic diameter (particulate matter begin subscript 2.5 end subscriptPM2.5)] and coarse particulate matter [less than or equal to 10 micrometers≤10μm in aerodynamic diameter (particulate matter begin subscript 10 end subscriptPM10)], nitrogen dioxide (nitrogen dioxideNO2), and carbon monoxide (CO)—with increased risk of incident CKD, eGFR decline, and progression to kidney failure,5–7 which requires dialysis or kidney transplantation for survival. Given that CKD is a leading cause of worldwide mortality and is usually asymptomatic until its advanced stages,4 elucidating the adverse kidney effects of air pollution and their pathogenesis may inform vital preventive strategies.In this issue of Environmental Health Perspectives, Lee et al. extend the potential risks of long-term air pollution exposure on kidney health to include acute kidney injury (AKI).8 They report the results of a longitudinal study of greater than 60 million>60 million Medicare beneficiaries, examining associations of long-term exposures to major air pollutants with risk of first hospitalization for AKI. They ascertained AKI status through hospital discharge diagnosis codes over 1-y periods of follow-up, which started from the participant’s entry into the cohort through the first admission with diagnosis codes for AKI, death, or the end of the study period, whichever came first. After adjustment for demographics and neighborhood-level socioeconomic status indicators, exposure to particulate matter begin subscript 2.5 end subscriptPM2.5, nitrogen dioxideNO2, and summertime ozone (ozoneO3) were each associated with increased risk of first hospitalization with AKI. Notably, these associations were attenuated in analyses restricted to participants presumed to have CKD; after restriction, only exposure to particulate matter begin subscript 2.5 end subscriptPM2.5 still indicated an increased risk with AKI hospitalization, although smaller than in the overall study population.The authors’ work draws welcome attention to the potential impact of air pollution on kidney disease, which had been relatively overlooked until the past few years. Most published studies have examined CKD,2,5–7 whereas AKI is a related but distinct condition (Figure 1), defined by an abrupt (within 48 h) and often reversible decline in GFR.9 Although prior work has associated short-term exposure to air pollution with increased risk of AKI,10 the broader causal and temporal relationships between air pollution and kidney disease remain to be defined.Figure 1. Relationship of air pollution, kidney disease, and select risk factors. Note: AKI, acute kidney injury; CKD, chronic kidney disease.The underlying biological mechanisms by which chronic exposure to air pollution could result in AKI are not fully clear, although a few possibilities exist. First, the proposed mechanisms that link air pollution to a gradual reduction in eGFR to result in CKD2—oxidative stress, systemic inflammation, DNA damage, and atherosclerosis—may increase susceptibility for AKI. The causes of AKI itself are vast and heterogenous, from hypotension and dehydration (accounting for up to 40% of hospital-acquired AKI globally11) to drugs, infection, ischemia, inflammation, vascular injury, and outflow obstruction.9 The pathogenic effects of air pollution may thus contribute to a “multi-hit” process that overwhelms the kidneys’ functional reserve to increase the risk of AKI. Second, the effects of air pollution on AKI may be mediated by comorbid conditions (Figure 1). These include hypertension, type 1 and type 2 diabetes,12,13 and even CKD, which markedly increases the risk for hospital-acquired AKI,14 and could explain why effect estimates in the present study were attenuated among participants with CKD. Last, air pollution could have acute, direct cytotoxic effects on the kidney akin to what has been proposed for iodinated contrast.15 This mechanism of kidney injury is plausible given studies in humans and mice showing that inhaled gold nanoparticles translocated from the lungs into systemic circulation and became detectable in the urine, indicating direct contact with the vasculature and tubules of the kidneys.16As recognized by the authors, the use of hospital discharge diagnosis codes to define AKI comes with important limitations. Although reasonably specific for adjudicated AKI events and convenient for health care research, these codes have poor sensitivity and undercount AKI incidence, including cases of AKI that occur without hospitalization.17 Moreover, diagnosis codes do not provide granularity on the cause of AKI or its timing relative to hospital admission. For instance, a participant’s AKI may a) be acquired in the community and be among the primary reasons for hospital admission, b) be absent on admission but develop quickly as a complication of the admitting diagnosis, or c) be absent on admission, but develop iatrogenically as a complication of the hospitalization, diagnostic interventions, or treatments. A direct causal role for air pollution in AKI, or increased susceptibility to AKI caused by exposure to air pollution, would be expected to have stronger relationships with AKI acquired in the community or early in the course of hospitalization, as well as with AKI caused by toxic or ischemic processes. Restriction to more specific AKI outcomes may help infer causal relationships and better quantify magnitudes of relevant associations.Accurate assessment of exposures and potential confounders are also critical for epidemiological inferences. Exposure assessments of ambient air pollution have historically relied on measurements from regulatory air monitoring stations operated by government agencies,18 which have been sparsely deployed in urban and populated regions to determine compliance with ambient air quality standards.19 Thus, improving air pollution assessment requires data sources other than the regulatory monitors, whether they are from satellite remote sensing data (a strength of the current study), investigator-led reference monitoring campaigns, or broadly deployed low-cost sensors. On confounding, air pollution, CKD, and AKI all share a common risk factor in socioeconomic status20–22—itself a complex construct with multiple domains—and interact with other characteristics and each other (Figure 1). Disentangling the true effects of air pollution on kidney disease is thus challenging but important. For example, it may well be that unmeasured behavioral or lifestyle factors contribute to hypertension and diabetes, two leading risk factors for CKD and AKI, as well as an increase in air pollution exposure that is then interpreted to “cause” the onset of AKI.Lee et al.8 contribute to the important and growing literature on the adverse kidney effects of air pollutants. Future studies that incorporate multiplatform data sources to improve exposure estimates, include more granular covariate data, and assess CKD and AKI concurrently and with increased granularity would help address some of the knowledge gaps posed above. Along with experimental studies aimed at identifying mechanisms of AKI, we may move closer toward a more holistic view of how air pollution affects the kidney.

Effects of dapagliflozin on hospitalisations in people with type 2 diabetes: post-hoc analyses of the DECLARE-TIMI 58 trial

In people with type 2 diabetes at high risk of cardiovascular or kidney disease, sodium-glucose co-transporter 2 (SGLT2) inhibitors consistently reduce the risk of hospitalisations for heart failure. Less is known about their effects on hospitalisation from any cause, especially in people with type 2 diabetes without atherosclerotic cardiovascular disease, which includes most of the global population of people with type 2 diabetes. We aimed to assess the effect of the SGLT2 inhibitor, dapagliflozin, on the risks of hospitalisations for any cause and for specific causes in people with type 2 diabetes with and without atherosclerotic cardiovascular disease. The DECLARE-TIMI 58 trial was a double-blind, multicentre, randomised, placebo-controlled study. People with type 2 diabetes and either risk factors for or established atherosclerotic cardiovascular disease were randomly assigned (1:1) to receive oral dapagliflozin 10 mg or placebo once daily. In these post-hoc analyses, the effects of dapagliflozin on risks of first non-elective any-cause and cause-specific hospitalisation were assessed with Cox proportional hazards regression models overall and in the subset of participants without prevalent atherosclerotic cardiovascular disease. The risk of total (first plus subsequent) non-elective hospitalisations was assessed with Lin-Wei-Ying-Yang model. Investigator-reported System Organ Class terms were used to classify cause-specific hospitalisations. The trial is registered with ClinicalTrials.gov, NCT01730534. Between April 25, 2013, and Sept 18, 2018, 17 160 people (6422 [37·4%] women, 10 738 [62·6%] men; mean age 63·9 years [SD 6·8]) were enrolled in the original trial, of whom 10186 (59·4%) had multiple risk factors for but did not have established atherosclerotic cardiovascular disease, and 6835 (39·8%) had both no evidence of atherosclerotic cardiovascular disease and low KDIGO risk. Over a median follow-up of 4·2 years (IQR 3·9-4·4), dapagliflozin was associated with a lower risk of first non-elective hospitalisation for any cause (2779 [32·4%] of 8582 people in the dapagliflozin group vs 3036 [35·4%] of 8578 people in the placebo group; hazard ratio [HR] 0·89 [95% CI 0·85-0·94]) and total (first plus subsequent) non-elective hospitalisations for any cause (risk ratio 0·92 [95% CI 0·86-0·97]). The association between dapagliflozin use and the risk of first non-elective hospitalisation for any cause was consistent in subgroups of participants with (HR 0·92 [95% CI 0·85-0·99] and without (0·87 [0·81-0·94]) atherosclerotic cardiovascular disease at baseline (p interaction=0·31). Compared with the placebo group, the dapagliflozin group had lower risk of first hospitalisations due to cardiac disorders (HR 0·91 [95% CI 0·84-1·00]), metabolism and nutrition disorders (0·73 [0·60-0·89]), renal and urinary disorders (0·61 [0·49-0·77]), and due to any other cause excluding these three causes (0·90 [0·85-0·96]). Treatment with dapagliflozin was also associated with a lower risk of hospitalisations due to musculoskeletal and connective tissue disorders (HR 0·81 [0·67-0·99]) and infections and infastations (HR 0·86 [0·78-0·96]). Dapagliflozin reduced the risk of first and total non-elective hospitalisations for any cause in people with type 2 diabetes, regardless of the presence of atherosclerotic cardiovascular disease, including hospitalisations not directly attributed to cardiac, kidney, or metabolic causes. These findings might have implications on health-related quality of life for people with type 2 diabetes and on health-care costs attributable this condition. AstraZeneca.

471 IMPACT OF COMPLETE REVASCULARIZATION ON DEVELOPMENT OF HEART FAILURE IN PATIENTS WITH ACUTE CORONARY SYNDROME AND MULTIVESSEL DISEASE

Abstract Background The impact of complete revascularization (CR) on survival and occurrence of heart failure (HF) after ACS is still unsettled. Goal of this study was to evaluate the impact of CR on HF hospitalization and adverse outcomes in patients with ACS and multivessel coronary artery disease undergoing PCI. Methods Consecutive ACS patients with multivessel disease from the CORALYS registry were included. First hospitalization for HF or cardiovascular (CV) death was the primary endpoint. Patients were stratified according to CR. Results Of 14699 patients in the CORALYS registry, 5054 had multivessel disease. 1473 (29.2%) underwent CR, while 3581 (70.8%) did not. Over 5 years follow-up, CR was associated with a reduced incidence of the primary endpoint (adjusted HR 0.66, 95% CI 0.51-0.85), first HF hospitalization (adj HR 0.67, 95% CI 0.49-0.90), CV death (adj HR 0.56, 95% CI 0.38-0.84) and all-cause death (adj HR 0.74, 95% CI 0.56-0.97). The results were consistent in the matched population and in the IPTW analysis. The benefit of CR was consistent across ACS presentations (HR 0.59, 95% CI 0.39-0.89 for STEMI and HR 0.71, 95% CI 0.50-0.99 for NSTE-ACS) and in patients with LVEF>40% (HR 0.52; 95% CI 0.37-0.72), while no significant benefit was observed in patients with LVEF≤40% (HR 0.77; 95% CI 0.37-1.10, p for interaction 0.04). Conclusions In patients with ACS and multivessel disease, CR reduced the risk of first hospitalization for HF and CV death, as well as first HF hospitalization, CV and overall death. When feasible, CR should be performed in all patients with ACS to reduce the incidence of HF and death. Future studies are needed to assess the evidence of CR in patients with depressed LVEF.

Timing of initiation of sodium-glucose co-transporter 2 inhibitor in patients with diabetes and chronic cardiac failure

Abstract Purpose Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of first hospitalization for heart failure (HHF) in patients with type 2 diabetes. We aimed to evaluate the impact of early initiation of SGLT2 inhibitors on recurrent HHF in diabetic patients with chronic cardiac failure. Methods We retrospectively analyzed 1,363 consecutive diabetic patients with chronic cardiac failure with index HHF between August 2015 and August 2020 in 16 public hospitals in Hong Kong who were prescribed SGLT2i (empagliflozin=1,009, 74% and dapagliflozin =354, 26%).Patients who initiated SGLT2i at discharge of index HHF were compared to those who were not. Risk of recurrent HHF was compared, using adjusted sub-distribution hazard ratios (aSHR) derived from Fine and Gray regression models, accounting for death as competing risk, adjusting for age, gender, concurrent medications. Comparisons were also conducted between initiation of SGLT2i ≤30 vs >30 days; and ≤90 vs. >90 days after discharge. Results Of 1,363 patients (mean age 63.9±11.6, female 34.6%), 85% had no history of previous HHF at enrollment, 11.9% had up to 2 and 3.1% and 3.1% ≥3 HHF in the past 5 years. SGLT2i was initiated in 37.4% of patients at discharge of index HHF and the median time from index HHF to SGLT2i initiation for the other patients was 4.2 (IQR: 0–20.4) months. During a median follow-up of 1.3 (IQR: 0.2–2.7) years, initiation of SGLT2i at discharge was associated with lower risk of recurrent HHF (aSHR = 0.79, 95% CI: 0.68–0.92). Similar effect was observed between SGLT2i initiation ≤30 vs. >30 days (aSHR = 0.82, 95% CI: 0.70–0.95) but not between ≤90 vs. >90 days (P=0.19). Conclusion Among patients with diabetes and chronic cardiac failure, the risk of recurrent HHF was reduced when SGLT2 was initiated early after index HHF. Funding Acknowledgement Type of funding sources: None.

Outcomes following severe acute respiratory syndrome coronavirus 2 infection among individuals with and without HIV in Denmark.

To compare the risk of a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test and coronavirus disease 2019 (COVID-19) outcomes in people with HIV (PWH) with the general population, and estimate the association with vaccination status. A nationwide, population based, matched cohort study. We included all Danish PWH ≥18 years ( n  = 5276) and an age and sex-matched general population cohort ( n  = 42 308). We used Cox regression analyses to calculate (adjusted) incidence rate ratios [(a)IRR] and further stratified and restricted the analyses. We observed no major difference in risk of first positive SARS-CoV-2 test [aIRR: 0.8 (95% confidence interval (CI): 0.8-0.9)], but a higher risk of first hospital contact with COVID-19 and hospitalization with severe COVID-19 for PWH vs. controls [IRR: 2.0; (1.6-2.5), 1.8 (1.4-2.3)]. Risk of first hospitalization decreased substantially in PWH with calendar time [first half of year 2022 vs. 2020 IRR: 0.3; (0.2-0.6)], whereas the risk compared to population controls remained almost twofold increased. We did not observe increased risk of death after SARS-CoV-2 infection [aIRR: 0.7 (95% CI: 0.3-2.0)]. Compared to PWH who had received two vaccines PWH who receiving a third vaccine had reduced risk of first positive SARS-CoV-2 test, death (individuals ≥60years) and hospitalization [aIRR: 0.9 (0.7-1.0); 0.2 (0.1-0.7); 0.6 (0.2-1.2)]. PWH have almost the same risk of a positive SARS-CoV-2 test as the general population. Although risk of hospital contacts and severe outcomes following SARS-CoV-2 infection is increased, the risk of death does not seem to be substantially increased. Importantly, a third vaccine is associated with reduced risk of infection, and death.

Healthcare resource utilization in patients treated with empagliflozin in East Asia.

ABSTRACTAims/IntroductionWe investigated the utilization of healthcare resources in patients with type 2 diabetes treated with empagliflozin, a sodium‐glucose co‐transporter‐2 (SGLT2) inhibitor, versus dipeptidyl peptidase‐4 (DPP‐4) inhibitors in clinical practice in Japan, South Korea, and Taiwan.Materials and MethodsWe analyzed the Japanese Medical Data Vision database (December 2014–April 2018), the South Korean National Health Information Database, and the Taiwanese National Health Insurance claims database (both May 2016–December 2017). Patients with type 2 diabetes starting empagliflozin, 10 or 25 mg, or a DPP‐4 inhibitor were matched 1:1 via propensity scores (PS). We compared inpatient care needs, emergency room (ER) visits, and outpatient visits between the treatment groups using Poisson regression and Cox proportional hazards models, pooled across countries by random‐effects meta‐analysis.ResultsWe identified 28,712 pairs of PS‐matched patients; the mean follow‐up was 5.7–6.8 months. Empagliflozin‐treated patients had a 27% lower risk of all‐cause hospitalization compared with DPP‐4 inhibitor–treated patients (rate ratio [RR] 0.73, 95% CI 0.67–0.79), and 23% reduced risk for first hospitalization (hazard ratio 0.77, 95% CI 0.73–0.81). The risk for an ER visit was 12% lower with empagliflozin than with DPP‐4 inhibitors (RR 0.88, 95% CI 0.83–0.94) while the risk for outpatient visit was 4% lower (RR 0.96, 95% CI 0.96–0.97). These findings were generally consistent across countries, regardless of baseline cardiovascular disease, and in the subgroup starting empagliflozin with the 10 mg dose.ConclusionsEmpagliflozin treatment was associated with lower inpatient care needs and other healthcare resource utilization than DPP‐4 inhibitors in routine clinical practice in East Asia in this study.

Total NT-proBNP, a novel biomarker related to recurrent atrial fibrillation

BackgroundNovel circulating biomarkers may help in understanding the underlying mechanisms of atrial fibrillation (AF), a challenge for AF management and prevention of cardiovascular (CV) events. Whether glycosylation affects the prognostic value of N-terminal pro-B type natriuretic peptide (NT-proBNP) in AF is still unknown.ObjectivesTo test how deglycosylated total NT-proBNP, NT-proBNP and a panel of biomarkers are associated with: (1) recurrent AF, (2) first hospitalization for CV reasons.MethodsA total of 382 patients of the GISSI-AF trial in sinus rhythm with a history of AF, echocardiographic variables, total NT-proBNP, NT-proBNP and nine additional biomarkers [Total N-terminal pro-B type natriuretic peptide (Total NT proBNP), N-terminal pro-B type natriuretic peptide (NTproBNP), Angiopoietin 2 (Ang2), Bone morphogenic protein-10 (BMP10), Dickkopf-related protein-3 (DKK3), Endothelial cell specific molecule-1 (ESM1), Fatty acid-binding protein 3 (FABP3), Fibroblast growth factor 23 (FGF23), Growth differentiation factor-15 (GDF15), Insulin-like growth factor-binding protein-7 (IGFBP7) and Myosin binding protein C3 (MYPBC3)]. were assayed at baseline, 6 and 12 months under blind conditions in a laboratory at Roche Diagnostics, Penzberg, Germany. The associations between circulating biomarkers and AF at the 6- and 12-month visits, and their predictive value, were assessed in multivariable models with logistic regression analysis and Cox proportional hazards regression analysis. Biomarkers associations were modelled for 1SD increase in their level.ResultsOver a median follow-up of 365 days, 203/382 patients (53.1%) had at least one recurrence of AF and 16.3% were hospitalized for CV reasons. Total NT-proBNP, NT-proBNP, Ang2 and BMP10 showed the strongest associations with ongoing AF. Natriuretic peptides also predicted recurrent AF (total NT-proBNP: HR:1.19[1.04–1.36], p = 0.026; NT-proBNP: HR:1.19[1.06–1.35], p = 0.016; Ang2: HR:1.07[0.95–1.20], p = 0.283; BMP10: HR:1.09[0.96–1.25], p = 0.249) and CV hospitalization (total NT-proBNP: HR:1.57[1.29–1.90], p < 0.001 1.63], p = 0.097).ConclusionsThe association of total NT-proBNP with the risk of AF first recurrence was similar to that of NT-proBNP, suggesting no influence of glycosylation. Analogous results were obtained for the risk of first hospitalization for CV reasons. Natriuretic peptides, Ang2 and BMP10 were associated with ongoing AF. Findings from the last two biomarkers point to a pathogenic role of cardiac extracellular matrix and cardiomyocyte growth in the myocardium of the right atrium and ventricle.

SGLT-2 inhibitors in patients with and without a history of heart failure: a meta-analysis

Abstract Background Sodium-glucose co-transporter 2 (SGLT-2) inhibitors emerged as a new groundbreaking therapy for patients with heart failure. Recent evidence showed significant benefits in patients with heart failure with reduced ejection fraction (HFrEF), regardless of diabetic status. Whether these medications also improve outcomes in patients without a history of heart failure or with heart failure with preserved ejection fraction (HFpEF) remains unknown. Purpose We sought to perform an updated meta-analysis of randomized controlled trials to evaluate the effects of SGLT-2 inhibitors on cardiovascular (CV) outcomes according to the history and type of heart failure. Methods All randomized, placebo-controlled trials of SGLT-2 inhibitors reporting similar CV outcomes were evaluated for inclusion. PubMed was searched from January 1, 2010 to February 1, 2021. Articles were independently reviewed and selected by two reviewers. The primary outcome was the composite of first hospitalization for heart failure and CV death. Secondary outcomes included its single components and all-cause mortality. Pooled hazard ratios (HR) and 95% confidence intervals (CI) were used as effect estimates and calculated with a random-effects model. Heterogeneity was assessed with the I2 index, and random-effects meta-regression was used to assess the interaction between treatment effect and history of heart failure and type of heart failure (HFrEF vs. HFpEF). Results Data from eight trials and a total of 56,665 patients (n=31,609 in SGLT-2 group, n=25,056 in placebo group) were included. Five studies enrolled high-risk patients with diabetes mellitus, while 3 studies enrolled patients with symptomatic heart failure. SGLT-2 inhibitors reduced the risk of first hospitalization for heart failure and CV death in patients with (HR 0.75 95% CI 0.70–0.81) and without (HR 0.78 95% CI 0.67–0.90; Figure 1) a history of heart failure. Similarly, patients with (HR 0.85 95% CI 0.78–0.93) or without (HR 0.85 95% CI 0.74–0.98) a history of heart failure treated with SGLT-2 inhibitors had a significant reduction in all-cause mortality. SGLT-2 inhibitors reduced the risk of CV death regardless of the history of heart failure, although the reduction was border-line statistically significant in patients without a history of heart failure (HR 0.81 95% CI 0.66–1.00; Figure 2). All subgroup interaction testing between patients with and without a history of heart failure was negative for all the above endpoints. Among patients with HFpEF, SGLT-2 inhibitors were associated with a nonsignificant trend towards reduced risk of the primary outcome (HR 0.80 95% CI 0.63–1.02). Conclusions SGLT-2 inhibitors significantly improve CV outcomes in patients with or without history of heart failure, and this effect seems to be consistent among those with HFrEF and HFpEF. Funding Acknowledgement Type of funding sources: None. Figure 1. CV death or HF hospitalizationFigure 2. Meta-analysis CV death

Iron Deficiency: A New Target for Patients With Heart Failure.

Iron deficiency (ID) is one of the most frequent comorbidities in patients with heart failure (HF). ID is estimated to be present in up to 50% of outpatients and is a strong independent predictor of HF outcomes. ID has been shown to reduce quality of life, exercise capacity and survival, in both the presence and absence of anemia. The most recent 2016 guidelines recommend starting replacement treatment at ferritin cutoff value <100 mcg/l or between 100 and 299 mcg/l when the transferrin saturation is <20%. Beyond its effect on hemoglobin, iron plays an important role in oxygen transport and in the metabolism of cardiac and skeletal muscles. Mitochondria are the most important sites of iron utilization and energy production. These factors clearly have roles in the diminished exercise capacity in HF. Oral iron administration is usually the first route used for iron repletion in patients. However, the data from the IRONOUT HF study do not support the use of oral iron supplementation in patients with HF and a reduced ejection fraction, because this treatment does not affect peak VO2 (the primary endpoint of the study) or increase serum ferritin levels. The FAIR-HF and CONFIRM-HF studies have shown improvements in symptoms, quality of life and functional capacity in patients with stable, symptomatic, iron-deficient HF after the administration of intravenous iron (i.e., FCM). Moreover, they have shown a decreased risk of first hospitalization for worsening of HF, as later confirmed in a subsequent meta-analysis. In addition, the EFFECT-HF study has shown an improvement in peak oxygen consumption at CPET (a parameter generally considered the gold standard of exercise capacity and a predictor of outcome in HF) in patients randomized to receive ferric carboxymaltose. Finally, the AFFIRM AHF trial evaluating the effects of FCM administration on the outcomes of patients hospitalized for acute HF has found significantly fewer hospital readmissions due to HF among patients treated with FCM rather than placebo.

Life Course Socioeconomic Status and Risk of Hospitalization for Heart Failure or Atrial Fibrillation in The Moli-Sani Study Cohort.

We investigated the association of cumulative socioeconomic disadvantage (CSD) and socioeconomic (SES) trajectories across life course with the risk of first hospitalization for heart failure (HF) or atrial fibrillation (AF) and tested some biological mechanisms in explaining such associations. Longitudinal analysis on 21,756 HF- and AF-free subjects recruited in the Moli-sani Study (2005-2010; Italy) and followed up for 8.2 years. CSD was computed using childhood SES, education and adulthood SES indicators, and the same were used to define overall trajectories. High disadvantage across life course (CSD≥8) posed subjects at increased risk of HF (Hazard ratio [HR]=2.58; 95%CI 1.78, 3.74) or AF (HR=1.57;1.05,2.33), as compared to low CSD. All explanatory factors accounted for 18.5% and 24% of the excess of HF and AF risks, respectively, associated with CSD. For subjects with low childhood SES, advancements in education lowered risk of HF (HR=0.70;0.48, 1.02) or AF (HR=0.50;0.28, 0.89), whereas achievements of adulthood SES were unlikely to contribute to disease reduction. In conclusion, a life-course disadvantaged SES is an important predictor of first hospitalization for HF and AF; known risk factors partially explained the SES-disease gradient. Upwardly mobile groups are likely to mitigate the effect of poor childhood circumstances especially through educational advancement.

Abstract 16285: Use of Non-steroidal Anti-inflammatory Drugs and Risk of First Hospitalization for Heart Failure in Diabetic Patients

Introduction: Patients with diabetes mellitus are prone to have heart failure (HF), either as new onset or worsening. Non-steroidal anti-inflammatory drugs (NSAIDs) cause sodium, water retention and increase the risk of HF. Hypothesis: NSAIDs associated risk of HF in diabetic patients has not been well evaluated. Methods: Cohort study with a nested case-control analysis was done based on the Korean National Health Insurance Service-Health Screening Cohort (NHIS-HEALS) database. Among overall 78,453 diabetic patients, 1569 cases with first hospitalization for HF were identified and compared with 1:10 matched controls (n = 15,325). Current user of NSAIDs was defined as the most recent prescription lasted until the index date or ended in the 30 days before the index date. Results: In HF group, mean age was older and tended to have more previous HF, ischemic heart disease compared to control. Current NSAIDs user was much higher in HF group compared with control (534, 34 % vs 3,778, 25%, p &lt; 0.001). The risk of a first hospital admission for HF associated with current use of NSAIDs was 1.60 (95% confidence interval (CI) 1.28 to 2.09) after controlling for major confounding factors. Multiple combination, high dose and injection of NSAIDs increased the risk of HF hospitalization (multiple combination; odds ratio (OR): 2.14, CI: 1.64 to 2.78, high dose; OR: 1.72, CI: 1.30 to 2.29, injection; OR: 2.36, CI: 1.79 to 3.09). NSAIDs associated risk of HF hospitalization was more significant, especially in diabetic patients with progressive diabetic retinopathy (OR: 2.23, CI 1.34 to 3.72) or overt neuropathy (OR: 4.59, CI: 2.84 to 7.43). Conclusions: Use of NSAIDs increased the risk of hospitalization for HF in diabetic patients, particularly with diabetic retinopathy and overt nephropathy as microvasculopathies. Therefore, the risk stratification for HF should be recommended in diabetic patients when the NSAIDs are prescribed.

To what extent is severe osteoarthritis preventable? Occupational and non-occupational risk factors for knee and hip osteoarthritis.

To explore the relative contribution of cumulative physical workload, sociodemographic and lifestyle factors, as well as prior injury to hospitalization due to knee and hip OA. We examined a nationally representative sample of persons aged 30-59 years, who participated in a comprehensive health examination (the Health 2000 Study). A total of 4642 participants were followed from mid-2000 to end-2015 for the first hospitalization due to knee or hip OA using the National Hospital Discharge Register. We examined the association of possible risk factors with the outcome using a competing risk regression model (death was treated as competing risk) and calculated population attributable fractions for statistically significant risk factors. Baseline age and BMI as well as injury were associated with the risk of first hospitalization due to knee and hip OA. Composite cumulative workload was associated with a dose-response pattern with hospitalizations due to knee OA and with hospitalizations due to hip OA at a younger age only. Altogether, prior injury, high BMI and intermediate to high composite cumulative workload accounted for 70% of hospitalizations due to knee OA. High BMI alone accounted for 61% and prior injury only for 6% of hospitalizations due to hip OA. Our results suggest that overweight/obesity, prior injury and cumulative physical workload are the most important modifiable risk factors that need to be targeted in the prevention of knee OA leading to hospitalization. A substantial proportion of hospitalizations due to hip OA can be reduced by controlling excess body weight.

27-OR: Effect of Canagliflozin on Total Hospitalization for Heart Failure Events in Patients with Type 2 Diabetes and Chronic Kidney Disease

Background: The sodium glucose co-transporter 2 inhibitor canagliflozin reduced the risk of first hospitalization for heart failure (HHF) in the CREDENCE trial. The prevention of recurrent events is important to patients, clinicians and payers. In this post-hoc analysis, we evaluated the effect of canagliflozin on total HHF events. Methods: The CREDENCE trial compared canagliflozin or matching placebo and followed patients for a median of 2.6 years. The study included 4401 participants with type 2 diabetes, substantial albuminuria and estimated glomerular filtration rate (eGFR) 30 to &amp;lt;90 ml/min/1.73 m2 receiving renin-angiotensin system blockade. Negative binomial regression models were performed to assess the effect of canagliflozin on the total number of HHF events. Results: The mean age of participants was 63 years, with a mean eGFR of 56.3 ml/min/1.73 m2, while 50% had a history of previous cardiovascular disease and 15% had a history of heart failure. During the trial, 230 people experienced 326 total HHF events, with 166 having 1 event, 43 having 2 events, 15 having 3 events, and 6 having ≥4 events; thus, 42% of those experiencing at least 1 event went on to suffer a recurrent event during the follow up. Canagliflozin reduced first HHF events by 39% (hazard ratio [HR], 0.61; 95% confidence interval [CI] 0.47-0.80; P &amp;lt;0.001; number needed to treat [NNT], 46; 95% CI 29-124) and total HHF events by 36% (event rates of 22.0 and 34.8 participants with an event/1000 patient-years with canagliflozin and placebo, respectively; incidence rate ratio [RR], 0.64; 95% CI 0.56-0.73; P &amp;lt;0.001). Conclusions: Canagliflozin significantly reduced first and recurrent HHF events. These findings provide further support for the benefit of continuing canagliflozin therapy after an index heart failure presentation to prevent recurrent HHF events. Disclosure J. Li: Employee; Self; George Institute. M.J. Jardine: Other Relationship; Self; See Other Relationship field. B. Neal: Research Support; Self; Janssen Research &amp; Development, LLC, Merck Schering Plough, Roche Pharma, Servier, Zydus Pharmaceuticals, Inc. Other Relationship; Self; Abbott, Janssen, Novartis, Pfizer, Roche, and Servier. H.L. Heerspink: Consultant; Self; AbbVie Inc., AstraZeneca, Boehringer Ingelheim International GmbH, CSL Behring, Gilead Sciences, Inc., Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., Mitsubishi Tanabe Pharma Corporation, Mundipharma International, Retrophin, Inc. C. Cannon: None. R. Agarwal: Other Relationship; Self; AbbVie Inc., Akebia Therapeutics, Amgen, AstraZeneca, Bayer Inc., Bird Rock Bio, Boehringer Ingelheim Pharmaceuticals, Inc., Celgene, Daiichi Sankyo, Eli Lilly and Company, GlaxoSmithKline plc., Ironwood Pharmaceuticals, Johnson &amp; Johnson, Merck &amp; Co., Inc., Novartis Pharmaceuticals Corporation, OPKO Health, Inc., Reata, Relypsa, Inc., Sandoz, Sanofi, Takeda Pharmaceutical Company Limited, ZS Pharma. G. Bakris: Consultant; Self; Alnylam, Merck &amp; Co., Inc., Relypsa, Inc., Teijin Pharma Limited. Other Relationship; Self; Bayer AG, Novo Nordisk Inc., Vascular Dynamics. D.M. Charytan: Advisory Panel; Self; Allena Pharmaceuticals, AstraZeneca, Merck &amp; Co., Inc., PLC Medical. Employee; Self; BAIM Institute. Research Support; Self; Janssen Pharmaceuticals, Inc. Other Relationship; Self; Baim, Amgen, Medtronic/Covidien, Zoll, Fresenius, Daiichi Sankyo, Douglas and London, Eli Lilly, Merck, Gilead, and Novo Nordisk. D. de Zeeuw: Advisory Panel; Self; AbbVie Inc., Bayer AG, Boehringer Ingelheim International GmbH, Fresenius Medical Care, Janssen Pharmaceuticals, Inc., Mitsubishi Tanabe Pharma Corporation. R. Edwards: Employee; Self; Janssen. T. Greene: Other Relationship; Self; Janssen, Durect, and Pfizer. A. Levin: Consultant; Self; Janssen Pharmaceuticals, Inc. Research Support; Self; AstraZeneca K.K., Boehringer Ingelheim Pharmaceuticals, Inc., Gilead Sciences, Inc. C.A. Pollock: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Otsuka Pharmaceutical Co., Ltd., Vifor Pharma Group. Research Support; Self; Diabetes Australia. Speaker’s Bureau; Self; AstraZeneca, Cipla Inc., MedErgy, Medscape, Mitsubishi Tanabe Pharma Corporation, Novartis AG, Otsuka Pharmaceutical Co., Ltd., Vifor Pharma Group. Other Relationship; Self; Amgen, George Institute for Global Health, Gilead Sciences, Inc., Janssen Pharmaceuticals, Inc. N. Rosenthal: None. D.C. Wheeler: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Reata. Consultant; Self; AstraZeneca, Bayer AG, GlaxoSmithKline, Janssen Pharmaceuticals, Inc. Speaker’s Bureau; Self; Amgen, Astellas Pharma Inc., Mundipharma International, Napp Pharmaceuticals. H. Zhang: Employee; Self; Renal Division of Peking University First Hospital. B. Zinman: Advisory Panel; Self; Abbott, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck Sharp &amp; Dohme Corp., Novo Nordisk Inc., Sanofi-Aventis. V. Perkovic: Other Relationship; Self; See Other Relationship field. K.W. Mahaffey: Consultant; Self; Medscape, Mitsubishi, Myokardia, NIH, Novartis, Novo Nordisk, Portola, Radiometer, Regeneron, SmartMedics, Springer Publishing, UCSF. Research Support; Self; Afferent, Amgen, Apple, Inc, AstraZeneca, Cardiva Medical, Inc, Daiichi, Ferring, Google (Verily), Johnson &amp; Johnson, Luitpold, Medtronic, Merck, NIH, Novartis, Sanofi, St. Jude, Tenax. C. Arnott: Employee; Self; George Institute for Global Health. Funding Janssen Research &amp; Development, LLC

Birth incidence, deaths and hospitalisations of children and young people with Down syndrome, 1990–2015: birth cohort study

ObjectiveTo investigate current Down syndrome live birth and death rates, and childhood hospitalisations, compared with peers.SettingGeneral community.ParticipantsAll live births with Down syndrome, 1990–2015, identified via Scottish regional cytogenetic laboratories, each...

Malnutrition risk and its association with adverse outcomes in a Belgian cohort of community-dwelling adults aged 80 years and over

ABSTRACT Objectives: To investigate the prevalence of malnutrition risk and its association with adverse outcomes in a Belgian cohort of community-dwelling adults aged ≥80 years, a worldwide growing age-group. Methods: In the BELFRAIL cohort, malnutrition risk was evaluated with the Mini Nutritional Assessment (MNA total score <24) and prealbumin levels (<20 mg/dl). Agreement between them was assessed with Kohen’s kappa coefficient. Association with first unplanned hospitalization (3.0 ± 0.25 years follow-up) and mortality (5.1 ± 0.25 years follow-up) was investigated with survival analysis and Cox multivariate regression. Results: Out of 567 BELFRAIL participants, 556 (98.1%) had MNA and 545 (96.1%) prealbumin levels. Sixty-eight (12.2%) were at risk of malnutrition based on MNA and 69 (12.7%) based on prealbumin, with very poor agreement between them (Kappa = 0.024, 95% CI −0.064, 0.112). For both MNA and prealbumin, participants with malnutrition risk had lower physical and cognitive performance tests' scores. They had no higher risk for first hospitalization compared to those without malnutrition risk, but higher risk for all-cause mortality even after adjustment for multimorbidity, inflammation, physical and mental functioning (HR 1.35 95%CI 0.92–1.97 for MNA; HR 1.46; 95%CI 1.01–2.12 for prealbumin). Conclusion: Malnutrition risk based on MNA or prealbumin was low in a Belgian cohort of community-dwelling adults aged ≥80 years. Physical and cognitive performance was lower in those with malnutrition risk, but malnutrition risk was not independently associated with hospitalization and mortality (except for malnutrition risk by prealbumin). Further research needs to investigate the best tool to assess malnutrition risk in this age group.

Combined healthy lifestyle factors and risk of all-cause and cardiovascular first hospitalization

Abstract Background We aimed to explore the association of combined healthy lifestyles with risk of first hospitalization for all-cause, cardiovascular disease (CVD), ischemic heart disease (IHD) and stroke in a southern Italian population-based cohort. We also investigated several biological mechanisms possibly on the pathway between lifestyles and health outcomes. Methods Longitudinal analysis on 23,161 men and women (aged≥35 y) recruited in the Moli-sani Study (2005-2010). We defined 4 healthy lifestyle factors as abstention from smoking; high adherence to Mediterranean diet; physical activity; absence of abdominal obesity. First hospital admissions for any and CVD-related causes were recorded by direct linkage with hospital discharge form registry. Hazard ratios (HR) with 95% confidence interval (95%CI) were calculated by multivariable Cox-regression. Results Over a median follow up of 7.2 y, we ascertained a total of 9,482 hospitalizations, 3,556 CVD, 939 IHD and 589 stroke-related hospital admissions. Adherence to all four healthy lifestyles, compared with none or 1, was associated with lower risk of hospitalization for any cause (HR = 0.82; 0.74-0.90), CVD (HR = 0.81;0.69-0.95) and IHD (HR = 0.63; 0.44-0.90) and, to a less extent, with stroke hospitalizations. Inflammatory biomarkers (e.g. C-reactive protein) were likely to partly explain the association between lifestyles and all-cause (14%) or CVD (15%) hospitalizations, while inflammation played a leading role towards risk of IHD (30%) and stroke-related hospital admissions (21%). Conclusions The impact of combined 4 healthy lifestyles on first hospitalization risk was considerable. Inflammatory biomarkers explained a large proportion of this association. Key messages Improvements to lifestyle reduce the risk of hospitalizations in a general adult population. Achieving a greater number of healthy behaviours has the potential to reduce the burden of hospitalizations and the associated healthcare costs.

Mediterranean diet and risk of first hospitalization for heart failure and atrial fibrillation

Abstract Background We aimed to explore the association of a traditional Mediterranean diet (MD) with risk of first hospitalization for heart failure (HF) or atrial fibrillation (AF) in a population-based cohort from a southern Italian region. Methods Longitudinal analysis on 20,598 men and women (aged≥35 y) free from HF, AF and cardiovascular disease recruited in the Moli-sani Study (2005-2010). First hospital admissions for HF or AF were recorded by direct linkage with hospital discharge form registry. Dietary data were collected by the EPIC food frequency questionnaire, adherence to MD was appraised by the Greek Mediterranean diet score (MDS ranging 0-9). Hazard ratios (HR) with 95% confidence interval (95%CI) were calculated by multivariable Cox-regression. Results Over a median follow up of 8.2 y, we ascertained 661 HF events and 337 AF cases. A 2-point increase in the MDS was associated with a downward trend in the risk of developing HF (HR = 0.94;0.85-1.04) after adjustment for potential confounders, while no association was found with risk of AF (HR = 1.07;0.94-1.21). Analyses run separately by gender revealed that higher adherence to an MD was associated with lower risk of HF among women (HF = 0.83;0.72-0.95 for 2-point increase in the MDS) but not in men (HR = 1.07;0.93-1.22; p for interaction=0.011). No gender-related difference was observed for AF risk (p for interaction=0.62). Among women, higher intake of monounsaturated over saturated fats was associated with 38% (20% to 52%) lower risk of HF, while in men moderate alcohol intake was likely to reduce HF risk (HR = 0.87;0.70-1.08). Conclusions Closer adherence to a traditional MD is associated with lower risk of first hospitalization for HF among women but not in men. No association was found with risk of AF. Key messages A traditional MD reduces the risk of HF in women but not in men. Minor dietary changes inspired to a traditional MD could be valuable primary prevention measures for risk of HF.

PCV142 ESTIMATING THE IMPACT ON RECURRENT HOSPITAL ADMISSIONS AND AMBULATORY VISITS OF PRESCRIBING FERRIC CARBOXYMALTOSE IN IRON DEFICIENCY PATIENTS WITH CHRONIC HEART FAILURE: A RETROSPECTIVE RWE STUDY USING A HOSPITAL REGISTRY IN SPAIN

Randomized placebo-controlled trials with Ferric Carboxymaltose (FCM) have shown a clinical benefit in the correction of iron deficiency (ID) in patients with Chronic Heart Failure (CHF). FCM is associated with significant improvements in functional capacity, symptoms and quality of life. Reduction in the risk of first hospitalization and recurrent hospitalization due to worsening heart failure were also identified. The aim of this study is to investigate if FCM therapy could be associated with a reduction of recurrent hospital admissions and ambulatory visits in routine clinical practice. A hospital registry in the Spanish NHS is used to analyze retrospectively data from 1,498 CHF patients. The hospital registry provides information of 1,498 patients (10,522 observations) from 2010 to 2019 with an average follow-up period of 4.02 years. The registry allows the extraction and analysis of data related to demographic and clinical characteristics, laboratory tests and healthcare resource use of two cohorts of CHF patients with ID: 317 patients who received intravenous iron-replacement therapy with FCM and 1,181 patients who did not receive FCM. The statistical method used was multilevel negative binomial regression with random intercept on patient ID and time follow-up as offset. The incidence rate of iron deficiency in the whole sample was 0.488 events per person-year. Treatment with FCM was strongly associated with a decrease in the rate of recurrent hospitalizations (IRR = 0.25, 95% CI 0.15-0.44; P <0.001), even after controlling for age, gender, diabetes, HF-ethiology, ferritin and TSAT. In addition, and compared to patients who received FCM, those with no treatment with FCM showed higher risk of ambulatory visits (IRR = 2.08, 95% CI 1.90-2.27; P <0.001) This study shows that intravenous FCM is associated with a reduction in recurrent hospitalizations and ambulatory visits for patients with iron deficiency and CHF in routine clinical practice.

Clinical outcomes stratified by baseline functional class after initial combination therapy for pulmonary arterial hypertension

BackgroundInitial combination therapy with ambrisentan and tadalafil reduced the risk of clinical failure events for treatment-naïve participants with pulmonary arterial hypertension (PAH) as compared to monotherapy. Previous studies in PAH have demonstrated greater treatment benefits in more symptomatic participants.MethodsAMBITION was an event-driven, double-blind study in which participants were randomized 2:1:1 to once-daily initial combination therapy with ambrisentan 10 mg plus tadalafil 40 mg, ambrisentan 10 mg plus placebo, or tadalafil 40 mg plus placebo. In this pre-specified subgroup analysis, we compared the efficacy data between those with functional class (FC) II vs. FC III symptoms at baseline.ResultsThis analysis included 500 participants in the previously defined primary analysis set (n = 155 FC II, n = 345 FC III). Comparing combination therapy to pooled monotherapy, the risk of clinical failure events was reduced by 79% (hazard ratio, 0.21 [95% confidence interval: 0.071, 0.63]) for FC II patients and 42% (hazard ratio, 0.58 [95% confidence interval: 0.39, 0.86]) for FC III patients. In a post-hoc analysis, the risk of first hospitalization for worsening PAH was also reduced by combination therapy, particularly for FC II patients (0 combination vs. 11 [14%] pooled monotherapy). Adverse events were frequent but comparable between the subgroups.ConclusionsTreatment benefit from initial combination therapy appeared at least as great for FC II as for FC III participants. Hospitalizations for worsening PAH were not observed in FC II participants assigned to combination. The present data support an initial combination strategy for newly diagnosed patients even when symptoms are less severe.Funded by Gilead Sciences, Inc. and GlaxoSmithKline; AMBITION ClinicalTrials.gov number, NCT01178073.