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Background: Heart failure guidelines have recently introduced a narrow category with mildly reduced left ventricular ejection fraction (LVEF) (heart failure with mildly reduced ejection fraction; LVEF 41%-49%) between the previous categories of reduced (heart failure with reduced ejection fraction; LVEF ≤40%) and preserved (heart failure with preserved ejection fraction; LVEF ≥50%) ejection fraction. Grouping of continuous measurements into narrow categories can be questioned if their variability is high., Methods and Results: We constructed a cohort of all 9716 new cases of chronic heart failure with an available LVEF in Stockholm, Sweden, from January 1, 2015, until December 31, 2020. All values of LVEF were collected over time, and patients were followed up until death, moving out of Stockholm, or end of study. Mixed models were used to quantify within-person variance in LVEF, and multistate Markov models, with death as an absorbing state, to quantify the stability of LVEF categories. LVEF values followed a normal distribution. The SD of the within-person variance in LVEF over time was 7.4%. The mean time spent in any LVEF category before transition to another category was on average <1 year for heart failure with mildly reduced ejection fraction. Probabilities of transitioning between categories during the first year were substantial; patients with heart failure with mildly reduced ejection fraction had a probability of <25% of remaining in that category 1 year later., Conclusions: LVEF follows a normal distribution and has considerable variability over time, which may impose a risk for underuse of efficient treatment. The heart failure with mildly reduced ejection fraction category is especially inconstant. Assumptions of a patient's current LVEF should take this variability and the normal distribution of LVEF into account.

Background: There are few contemporary data on outcomes, costs, and treatment following a hospitalization for heart failure (hHF) in epidemiologically representative cohorts., Objectives: This study sought to describe rehospitalizations, hospitalization costs, use of guideline-directed medical therapy (GDMT) (renin-angiotensin system inhibitors, sacubitril/valsartan, beta-blockers, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter-2 inhibitors), and mortality after hHF., Methods: EVOLUTION HF (Utilization of Dapagliflozin and Other Guideline Directed Medical Therapies in Heart Failure Patients: A Multinational Observational Study Based on Secondary Data) is an observational, longitudinal cohort study using data from electronic health records or claims data sources in Japan, Sweden, the United Kingdom, and the United States. Adults with a first hHF discharge between 2018 and 2022 were included. The 1-year event rates per 100 patient-years (ERs) for death and rehospitalizations (with a primary diagnosis of heart failure (HF), chronic kidney disease [CKD], myocardial infarction, stroke, or peripheral artery disease) were calculated. Hospital health care costs were cumulatively summarized. Cumulative GDMT use was assessed using Kaplan-Meier estimates., Results: Of 263,525 patients, 28% died within the first year post-hHF (ER: 28.4 [95% CI: 27.0-29.9]). Rehospitalizations were mainly driven by HF (ER: 13.6 [95% CI: 9.8-17.4]) and CKD (ER: 4.5 [95% CI: 3.6-5.3]), whereas the ERs for myocardial infarction, stroke, and peripheral artery disease were lower. Health care costs were predominantly driven by HF and CKD. Between 2020 and 2022, use of renin-angiotensin system inhibitors, sacubitril/valsartan, beta-blockers, and mineralocorticoid receptor antagonists changed little, whereas uptake of sodium-glucose cotransporter-2 inhibitors increased 2- to 7-fold., Conclusions: Incident post-hHF rehospitalization risks and costs were high, and GDMT use changed little in the year following discharge, highlighting the need to consider earlier and greater implementation of GDMT to manage risks and reduce costs., Competing Interests: Funding Support and Author Disclosures EVOLUTION HF is funded by AstraZeneca. Dr Cleland was supported by a British Heart Foundation Centre of Research Excellence (grant number RE/18/6/34217). Dr Bozkurt has received consulting, advisory or research support from Abbott Vascular, Amgen, AstraZeneca, Baxter Healthcare Corporation, Boehringer Ingelheim, Bristol Myers Squibb, Cardurion, Liva Nova, Relypsa, Renovacor, Roche, Sanofi, scPharmaceuticals, and Vifor. Dr Savarese has received grants from AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Merck, Novartis, Pharmacosmos, and Vifor; and personal fees from AstraZeneca, Cytokinetics, Edwards Lifesciences, Medtronic, Novartis, Pharmacosmos, Roche, Laboratoires Servier, and Vifor. Drs Adamsson Eryd, Bodegård, Khordoc, and Zhang are employees of AstraZeneca. Dr Cleland has received grants and/or personal fees from Abbott Laboratories, Amgen, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Bristol Myer Squibb, Idorsia, Johnson & Johnson, Medtronic, MyoKardia, NI Medical, Novartis, Pharmacosmos, Pharma Nord, Respicardia, Laboratoires Servier, Torrent Pharmaceuticals, Vifor, and VisCardia. Dr Thuresson is an employee of Statisticon, which has received funding from AstraZeneca. Dr Vardeny has received personal or institutional research support from AstraZeneca. Dr Lund has received grant support, lecture fees, and/or consulting fees from Abbott Laboratories, Alleviant, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Edwards Lifesciences, Lexicon Pharmaceuticals, Medscape, Merck Sharp & Dohme, MyoKardia, Novartis, OrionPharma, Pharmacosmos, Sanofi, and Vifor. Dr Kishi has reported that he has no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: To explore how cardiorenal disease (CRD; heart failure and/or chronic kidney disease) impacted mortality in men and women hospitalised for COVID-19 during the first three waves of the pandemic in Sweden in comparison to previous influenza outbreaks., Design: A registry-based, retrospective, case-control study., Setting: Hospital care in Sweden., Participants: All patients in Sweden with a main hospital diagnosis of COVID-19 (January 2020-September 2021) or influenza (January 2015-December 2019) with previous CRD were identified in registries and compared with a reference group free from CRD but with COVID-19 or influenza., Primary Outcome Measure: Associated risk of all-cause death during the first year was analysed using adjusted Cox proportional hazards models., Results: In COVID-19 patients with and without prior history of CRD (n=44 866), mean age was 79.8 years (SD 11.8) and 43% were women. In influenza patients (n=8897), mean age was 80.6 years (SD 11.5) and 45% were women. COVID-19 versus influenza was associated with higher mortality risk during the first two COVID-19 waves (HR 1.53; 95% CI 1.45 to 1.62, p<0.001 and HR 1.52; 95% CI 1.44 to 1.61, p<0.001), but not in the third wave (HR 1.07; 95% CI 0.99 to 1.14, p=0.072). CRD was an independent risk factor for all-cause death after COVID-19 in men and women (men: 1.37; 95% CI 1.31 to 1.44, p<0.001; women: 1.46; 95% CI 1.38 to 1.54, p<0.001). At ages <70 years, women with CRD had a similar mortality rate to men with CRD, while at ages ≥70 years, the mortality rate was higher in men., Conclusions: Outcome after COVID-19 is worse if CRD is present. In women at ages <70 years, the presence of CRD attenuates the protective effect of female sex. COVID-19 was associated with higher mortality risk than influenza during the first two pandemic waves., Competing Interests: Competing interests: The authors declared the following potential conflicts of interest with respect to the research, authorship and publication of this article: VR has received honoraria on expert group participation from Astra Zeneca, Novo Nordisk and Boehringer Ingelheim. AN has received honoraria from Astra Zeneca, Merck Sharp & Dohme, Eli Lilly and Company, Novo Nordisk and Boehringer Ingelheim on expert group participation. TN has received unrestricted grants from AstraZeneca and NovoNordisk and has served on national advisory boards of Abbot, Amgen, Novo Nordisk, Sanofi-Aventis, Eli Lilly, MSD and Boehringer Ingelheim. JE has received research support or honoraria from AstraZeneca, NovoNordisk, Bayer, Ilya Pharma, Merck-Sharp & Dohme, Boehringer-Ingelheim. RK and DN reports no conflicts of interest. JB holds a full-time position at AstraZeneca as an epidemiologist. MT holds a full-time position by an independent statistical consultant company, Statisticon AB, Uppsala, Sweden, of which AstraZeneca Nordic is a client., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Guidelines recommend early initiation of multiple guideline-directed medical therapies (GDMTs) to reduce mortality/rehospitalization in patients with heart failure and reduced ejection fraction. Understanding GDMT use is critical to improving clinical practice., Objectives: This study sought to describe GDMT use in Japan, Sweden, and the United States in contemporary real-world settings., Methods: EVOLUTION HF (Utilization of Dapagliflozin and Other Guideline Directed Medical Therapies in Heart Failure Patients: A Multinational Observational Study Based on Secondary Data) is an observational cohort study using routine-care databases. Patients initiating any GDMT within 12 months of a hospitalization for heart failure (hHF) discharge were included. Dapagliflozin (the only sodium-glucose cotransporter-2 inhibitor approved at study onset), sacubitril/valsartan, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, and mineralocorticoid receptor antagonists (MRAs) were considered separately. Doses and discontinuation were assessed in the 12 months following initiation. Target dose was defined as ≥100% of the guideline-recommended dose., Results: Overall, 266,589 patients were included. Mean times from hHF to GDMT initiation were longer for novel GDMTs (dapagliflozin or sacubitril/valsartan) than for other GDMTs: 39 and 44 vs 12 to 13 days (Japan), 44 and 33 vs 22 to 31 days (Sweden), and 33 and 19 vs 18 to 24 days (United States). Pooled across countries, proportions of patients who discontinued therapy (not including switches from ACE inhibitor or ARB to sacubitril/valsartan) within 12 months were 23.5% (dapagliflozin), 26.4% (sacubitril/valsartan), 38.4% (ACE inhibitors), 33.4% (ARBs), 25.2% (beta-blockers), and 42.2% (MRAs). Corresponding target dose achievements were 75.7%, 28.2%, 20.1%, 6.7%, 7.2%, and 5.1%, respectively., Conclusions: Initiation of novel GDMTs is delayed compared with other GDMTs. Few patients received target doses of GDMTs requiring uptitration. Persistence was higher for dapagliflozin than other GDMTs., Competing Interests: Funding Support and Author Disclosures EVOLUTION HF is funded by AstraZeneca. Dr Savarese has received grants from AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Merck, Novartis, Pharmacosmos, and Vifor; and personal fees from AstraZeneca, Cytokinetics, Medtronic, Pharmacosmos, Roche, Servier, and Vifor. Dr Vardeny has received personal or institutional research support from AstraZeneca. Drs Adamsson Eryd and Bodegård are employees of AstraZeneca. Dr Lund has received grant support, lecture fees, and consulting fees from AstraZeneca. Dr Thuresson is an employee of Statisticon, which has received funding from AstraZeneca. Dr Bozkurt has received consulting fees from Amgen, AstraZeneca, Bristol Myers Squibb, scPharmaceuticals, Baxter, Sanofi, Relypsa, Vifor, Roche, and Boehringer Ingelheim; has served on the steering committees of Relypsa and Renovacor; has served on a Clinical Event Committee for Abbott Pharmaceuticals; and has served on the Data Safety Monitoring Board for LivaNova Pharmaceuticals. Dr Kishi has reported that he has no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Type-2 diabetes (T2D), chronic kidney disease, and heart failure (HF) share epidemiological and pathophysiological features. Although their prevalence was described, there is limited contemporary, high-resolution, epidemiological data regarding the overlap among them. We aimed to describe the epidemiological intersections between T2D, HF, and kidney dysfunction in an entire database, overall and by age and sex., Methods: This is a cross-sectional analysis of adults ≥ 25 years, registered in 2019 at Maccabi Healthcare Services, a large healthcare maintenance organization in Israel. Collected data included sex, age, presence of T2D or HF, and last estimated glomerular filtration rate (eGFR) in the past two years. Subjects with T2D, HF, or eGFR < 60 mL/min/1.73 m 2 were defined as within the diabetes-cardio-renal (DCR) spectrum., Results: Overall, 1,389,604 subjects (52.2% females) were included; 445,477 (32.1%) were 25- < 40 years, 468,273 (33.7%) were 40- < 55 years, and 475,854 (34.2%) were ≥ 55 years old. eGFR measurements were available in 74.7% of the participants and in over 97% of those with T2D or HF. eGFR availability increased in older age groups. There were 140,636 (10.1%) patients with T2D, 54,187 (3.9%) with eGFR < 60 mL/min/1.73m 2 , and 11,605 (0.84%) with HF. Overall, 12.6% had at least one condition within the DCR spectrum, 2.0% had at least two, and 0.23% had all three. Cardiorenal syndrome (both HF and eGFR < 60 mL/min/1.73m 2 ) was prevalent in 0.40% of the entire population and in 2.3% of those with T2D. In patients with both HF and T2D, 55.2% had eGFR < 60 mL/min/1.73m 2 and 15.8% had eGFR < 30 mL/min/1.73m 2 . Amongst those within the DCR spectrum, T2D was prominent in younger participants, but was gradually replaced by HF and eGFR < 60 mL/min/1.73m 2 with increasing age. The congruence between all three conditions increased with age., Conclusions: This large, broad-based study provides a contemporary, high-resolution prevalence of the DCR spectrum and its components. The results highlight differences in dominance and degree of congruence between T2D, HF, and kidney dysfunction across ages., (© 2022. The Author(s).)

Aims: To examine heart failure (HF) and chronic kidney disease (CKD) risks reduction associated with sodium-glucose cotransporter-2 inhibitors (SGLT-2i) compared to other glucose-lowering drugs (oGLD) in the early stage of type 2 diabetes patients without established cardiovascular or renal diseases (CVRD-free T2D)., Materials and Methods: We performed an observational cohort study using a Japanese hospital claims registry, Medical Data Vision. CVRD-free T2D patients were identified between 1 April 2014 and 30 September 2018. SGLT-2i and oGLD new users (and dipeptidyl peptidase 4 inhibitors [DPP-4i] separately) were subjected to 1:1 propensity-score matching analysis. Hazard ratios (HRs) of cardiorenal disease (HF and/or CKD), HF, CKD, stroke, myocardial infarction (MI), and all-cause mortality, were estimated using unadjusted Cox regression., Results: A total of 108 362 CVRD-free patients including 54 181 SGLT-2i and 54 181 oGLD users were matched. Baseline characteristics were well balanced (mean age 59.1 years, 63% male, and follow-up 1.50 years [162 970 patient-years]). Compared to oGLD group, SGLT-2i group had lower risk of cardiorenal disease, HF, CKD, stroke, and all-cause mortality with HRs (95% confidence intervals) 0.55 (0.49-0.61), 0.73 (0.61-0.87), 0.45 (0.39-0.52), 0.69 (0.59-0.81), and 0.52 (0.46-0.58), respectively, while no difference in MI. These were consistent in 1:1 propensity-score matching analysis between SGLT-2i and DPP-4i users (n = 17 232 in each group)., Conclusions: In Japanese CVRD-free T2D patients, SGLT-2i initiation was associated with lower risk of cardiorenal diseases, stroke, and all-cause mortality compared to oGLD, suggesting preventive effect of SGLT-2i treatment in the early stage of T2D patients without CVRD manifestation., (© 2021 John Wiley & Sons Ltd.)

Background: Reduction in cardiovascular death and hospitalization for heart failure (HHF) was recently reported with the sodium-glucose cotransporter-2 inhibitor (SGLT-2i) empagliflozin in patients with type 2 diabetes mellitus who have atherosclerotic cardiovascular disease. We compared HHF and death in patients newly initiated on any SGLT-2i versus other glucose-lowering drugs in 6 countries to determine if these benefits are seen in real-world practice and across SGLT-2i class., Methods: Data were collected via medical claims, primary care/hospital records, and national registries from the United States, Norway, Denmark, Sweden, Germany, and the United Kingdom. Propensity score for SGLT-2i initiation was used to match treatment groups. Hazard ratios for HHF, death, and their combination were estimated by country and pooled to determine weighted effect size. Death data were not available for Germany., Results: After propensity matching, there were 309 056 patients newly initiated on either SGLT-2i or other glucose-lowering drugs (154 528 patients in each treatment group). Canagliflozin, dapagliflozin, and empagliflozin accounted for 53%, 42%, and 5% of the total exposure time in the SGLT-2i class, respectively. Baseline characteristics were balanced between the 2 groups. There were 961 HHF cases during 190 164 person-years follow-up (incidence rate, 0.51/100 person-years). Of 215 622 patients in the United States, Norway, Denmark, Sweden, and the United Kingdom, death occurred in 1334 (incidence rate, 0.87/100 person-years), and HHF or death in 1983 (incidence rate, 1.38/100 person-years). Use of SGLT-2i, versus other glucose-lowering drugs, was associated with lower rates of HHF (hazard ratio, 0.61; 95% confidence interval, 0.51-0.73; P <0.001); death (hazard ratio, 0.49; 95% confidence interval, 0.41-0.57; P <0.001); and HHF or death (hazard ratio, 0.54; 95% confidence interval, 0.48-0.60; P <0.001) with no significant heterogeneity by country., Conclusions: In this large multinational study, treatment with SGLT-2i versus other glucose-lowering drugs was associated with a lower risk of HHF and death, suggesting that the benefits seen with empagliflozin in a randomized trial may be a class effect applicable to a broad population of patients with type 2 diabetes mellitus in real-world practice., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02993614., (© 2017 The Authors.)

Aims: To investigate cardiovascular (CV) safety and event rates for dapagliflozin versus other glucose‐lowering drugs (GLDs) in a real‐world type 2 diabetes population after applying the main inclusion criteria and outcomes from the DECLARE‐TIMI 58 study. Methods: Patients with new initiation of dapagliflozin and/or other GLDs were identified in Swedish nationwide healthcare registries for the period 2013 to 2016. Patients were included if they met the main DECLARE‐TIMI 58 inclusion criteria: age ≥40 years and established CV disease or presence of multiple‐risk factors, e.g. men aged ≥55 years and women aged ≥60 years with hypertension or dyslipidaemia. Propensity scores for the likelihood of dapagliflozin initiation were calculated, then 1:3 matching was carried out. DECLARE‐TIMI 58 outcomes were hospitalization for heart failure (HHF) or CV‐specific mortality, and major adverse CV events (MACE; CV‐specific mortality, myocardial infarction, or stroke). Cox survival models were used to estimate hazard ratios (HRs). Results: After matching, a total of 28 408 new‐users of dapagliflozin and/or other GLDs were identified, forming the population for the present study (henceforth referred to as the DECLARE‐like cohort. The mean age of this cohort was 66 years, and 34% had established CV disease. Dapagliflozin was associated with 21% lower risk of HHF or CV mortality versus other GLDs (HR 0.79, 95% confidence interval [CI] 0.69‐0.92) and had no significant association with MACE (HR 0.90, 95% CI 0.79‐1.03). HHF and CV mortality risks, separately, were lower at HR 0.79 (95% CI 0.67‐0.93) and HR 0.75 (95% CI 0.57‐0.97), respectively. Non‐significant associations were seen for myocardial infarction and stroke: HR 0.91 (95% CI 0.74‐1.11) and HR 1.06 (95% CI 0.87‐1.30), respectively. Conclusion: In a real‐world population similar to those included in the DECLARE‐TIMI 58 study, dapagliflozin was safe with regard to CV outcomes and resulted in lower event rates of HHF and CV mortality versus other GLDs. [ABSTRACT FROM AUTHOR]

The multinational, observational CVD‐REAL study recently showed that initiation of sodium‐glucose co‐transporter‐2 inhibitors (SGLT‐2i) was associated with significantly lower rates of death and heart failure vs other glucose‐lowering drugs (oGLDs). This sub‐analysis of the CVD‐REAL study sought to determine the association between initiation of SGLT‐2i vs oGLDs and rates of myocardial infarction (MI) and stroke. Medical records, claims and national registers from the USA, Sweden, Norway and Denmark were used to identify patients with T2D who newly initiated treatment with SGLT‐2i (canagliflozin, dapagliflozin or empagliflozin) or oGLDs. A non‐parsimonious propensity score was developed within each country to predict initiation of SGLT‐2i, and patients were matched 1:1 in the treatment groups. Pooled hazard ratios (HRs) and 95% CIs were generated using Cox regression models. Overall, 205 160 patients were included. In the intent‐to‐treat analysis, over 188 551 and 188 678 person‐years of follow‐up (MI and stroke, respectively), there were 1077 MI and 968 stroke events. Initiation of SGLT‐2i vs oGLD was associated with a modestly lower risk of MI and stroke (MI: HR, 0.85; 95%CI, 0.72‐1.00; P = .05; Stroke: HR, 0.83; 95% CI, 0.71‐0.97; P = .02). These findings complement the results of the cardiovascular outcomes trials, and offer additional reassurance with regard to the cardiovascular effects of SGLT‐2i, specifically as it relates to ischaemic events. [ABSTRACT FROM AUTHOR]