Unraveling the relationships between alpha- and beta-adrenergic modulation and the risk of heart failure.

Background: The effects of α and ß adrenergic receptor modulation on the risk of developing heart failure (HF) remains uncertain due to a lack of randomized controlled trials. This study aimed to estimate the effects of α and ß adrenergic receptors modulation on the risk of HF and to provide proof of principle for genetic target validation studies in HF. Methods: Genetic variants within the cis regions encoding the adrenergic receptors α1A, α2B, ß1, and ß2 associated with blood pressure in a 757,601-participant genome-wide association study (GWAS) were selected as instruments to perform a drug target Mendelian randomization study. Effects of these variants on HF risk were derived from the HERMES GWAS (542,362 controls; 40,805 HF cases). Results: Lower α1A or ß1 activity was associated with reduced HF risk: odds ratio (OR) 0.83 (95% CI 0.74-0.93, P = 0.001) and 0.95 (95% CI 0.93-0.97, P = 8 × 10-6). Conversely, lower α2B activity was associated with increased HF risk: OR 1.09 (95% CI 1.05-1.12, P = 3 × 10-7). No evidence of an effect of lower ß2 activity on HF risk was found: OR 0.99 (95% CI 0.92-1.07, P = 0.95). Complementary analyses showed that these effects were consistent with those on left ventricular dimensions and acted independently of any potential effect on coronary artery disease. Conclusions: This study provides genetic evidence that α1A or ß1 receptor inhibition will likely decrease HF risk, while lower α2B activity may increase this risk. Genetic variant analysis can assist with drug development for HF prevention.

Associations between baseline heart rate and blood pressure and time to events in heart failure with reduced ejection fraction patients: Data from the QUALIFY international registry.

AIMS: A high resting heart rate (RHR) and low systolic blood pressure (SBP) are a risk factor and a risk indicator, respectively, for poor heart failure (HF) outcomes. This analysis evaluated the associations between baseline RHR and SBP with outcomes and treatment patterns in patients with HF and reduced ejection fraction (HFrEF) in the QUALIFY (QUality of Adherence to guideline recommendations for LIFe-saving treatment in heart failure surveY) international registry. METHODS AND RESULTS: Between September 2013 and December 2014, 7317 HFrEF patients with a previous HF hospitalization within 1-15 months were enrolled in the QUALIFY registry. Complete follow-up data were available for 5138 patients. The relationships between RHR and SBP and outcomes were assessed using a Cox proportional hazards model and were analysed according to baseline values as high RHR (H-RHR) ≥75 bpm versus low RHR (L-RHR) <75 bpm and high SBP (H-SBP) ≥110 mmHg versus low SBP (L-SBP) <110 mmHg and analysed according to each of the following four phenotypes: H-RHR/L-SBP, L-RHR/L-SBP, H-RHR/H-SBP and L-RHR/H-SBP (reference group). Compared to the reference group, H-RHR/L-SBP was associated with the worst outcomes for the combined primary endpoint of cardiovascular death and HF hospitalization (hazard ratio [HR] 1.83, 95% confidence interval [CI] 1.51-2.21, p < 0.001), cardiovascular death (HR 2.70, 95% CI 1.69-4.33, p < 0.001), and HF hospitalization (HR 1.62, 95% CI 1.30-2.01, p < 0.001). Low-risk patients with L-RHR/H-SBP achieved more frequently ≥50% of target doses of angiotensin-converting enzyme inhibitors (ACEIs) and beta-blockers (BBs) than the other groups. However, 48% and 46% of low-risk patients were not well treated with ACEIs and BBs, respectively (≤50% of target dose or no treatment). CONCLUSION: In patients with HFrEF and recent hospitalization, elevated RHR and lower SBP identify patients at increased risk for cardiovascular endpoints. While SBP and RHR are often recognized as barriers that deter physicians from treating with high doses of recommended drugs, they are not the only reason leaving many patients suboptimally treated.

[Introduction of treatments for heart failure and reduced ejection fraction under 50 % : In-hospital optimization using an algorithmic approach]. / Introduction hospitalière des traitements de l'insuffisance cardiaque à fraction d'éjection altérée < 50 % : mise au point et proposition d'algorithme.

Recent international guidelines recommend rapid initiation and titration of basic treatments of heart failure but do not explain how to achieve this goal. Despite these recommendations, implementation of treatment in daily practice is poor. This may be partly explained by the profile of the patients (frailty, comorbidities), safety considerations and tolerability issues related to kydney function, low blood pressure or heart rate and hyperkalaemia. In this special article, we intended to help the physician, through an algorithmic approach, to quickly and safely introduce guideline-directed medical therapy in the field of heart failure with ejection fraction under 50%.

Effect of Sotagliflozin on Early Mortality and Heart Failure-Related Events: A Post Hoc Analysis of SOLOIST-WHF.

BACKGROUND: Approximately 25% of patients admitted to hospitals for worsening heart failure (WHF) are readmitted within 30 days. OBJECTIVES: The authors conducted a post hoc analysis of the SOLOIST-WHF (Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post-WHF) trial to evaluate the efficacy of sotagliflozin versus placebo to decrease mortality and HF-related events among patients who began study treatment on or before discharge from their index hospitalization. METHODS: The main endpoint of interest was cardiovascular death or HF-related event (HF hospitalization or urgent care visit) occurring within 90 and 30 days after discharge for the index WHF hospitalization. Treatment comparisons were by proportional hazards models, generating HRs, 95% CIs, and P values. RESULTS: Of 1,222 randomized patients, 596 received study drug on or before their date of discharge. Sotagliflozin reduced the main endpoint at 90 days after discharge (HR: 0.54 [95% CI: 0.35-0.82]; P = 0.004) and at 30 days (HR: 0.49 [95% CI: 0.27-0.91]; P = 0.023) and all-cause mortality at 90 days (HR: 0.39 [95% CI: 0.17-0.88]; P = 0.024). In subgroup analyses, sotagliflozin reduced the 90-day main endpoint regardless of sex, age, estimated glomerular filtration rate, N-terminal pro-B-type natriuretic peptide, left ventricular ejection fraction, or mineralocorticoid receptor agonist use. Sotagliflozin was well-tolerated but with slightly higher rates of diarrhea and volume-related events than placebo. CONCLUSIONS: Starting sotagliflozin before discharge in patients with type 2 diabetes hospitalized for WHF significantly decreased cardiovascular deaths and HF events through 30 and 90 days after discharge, emphasizing the importance of beginning sodium glucose cotransporter treatment before discharge.

Efficacy of ivabradine in heart failure patients with a high-risk profile (analysis from the SHIFT trial).

AIMS: Early start and patient profile-oriented heart failure (HF) management has been recommended. In this post hoc analysis from the SHIFT trial, we analysed the treatment effects of ivabradine in HF patients with systolic blood pressure (SBP) < 110 mmHg, resting heart rate (RHR) ≥ 75 b.p.m., left ventricular ejection fraction (LVEF) ≤ 25%, New York Heart Association (NYHA) Class III/IV, and their combination. METHODS AND RESULTS: The SHIFT trial enrolled 6505 patients (LVEF ≤ 35% and RHR ≥ 70 b.p.m.), randomized to ivabradine or placebo on the background of guideline-defined standard care. Compared with placebo, ivabradine was associated with a similar relative risk reduction of the primary endpoint (cardiovascular death or HF hospitalization) in patients with SBP < 110 and ≥110 mmHg [hazard ratio (HR) 0.89, 95% confidence interval (CI) 0.74-1.08 vs. HR 0.80, 95% CI 0.72-0.89, P interaction = 0.34], LVEF ≤ 25% and >25% (HR 0.85, 95% CI 0.72-1.01 vs. HR 0.80, 95% CI 0.71-0.90, P interaction = 0.53), and NYHA III-IV and II (HR 0.83, 95% CI 0.74-0.94 vs. HR 0.81, 95% CI 0.69-0.94, P interaction = 0.79). The effect was more pronounced in patients with RHR ≥ 75 compared with <75 (HR 0.76, 95% CI 0.68-0.85 vs. HR 0.97, 95% CI 0.81-0.1.16, P interaction = 0.02). When combining these profiling parameters, treatment with ivabradine was also associated with risk reductions comparable with patients with low-risk profiles for the primary endpoint (relative risk reduction 29%), cardiovascular death (11%), HF death (49%), and HF hospitalization (38%; all P values for interaction: 0.40). No safety concerns were observed between study groups. CONCLUSIONS: Our analysis shows that RHR reduction with ivabradine is effective and improves clinical outcomes in HF patients across various risk indicators such as low SBP, high RHR, low LVEF, and high NYHA class to a similar extent and without safety concern.

Time to benefit of heart rate reduction with ivabradine in patients with heart failure and reduced ejection fraction.

AIMS: In the SHIFT (Systolic Heart failure treatment with the If inhibitor ivabradine Trial, ISRCTN70429960) study, ivabradine reduced cardiovascular death or heart failure (HF) hospitalizations in patients with HF and reduced ejection fraction (HFrEF) in sinus rhythm and with a heart rate (HR) ≥70 bpm. In this study, we sought to determine the clinical significance of the time durations of HR reduction and the significant treatment effect on outcomes among patients with HFrEF. METHODS AND RESULTS: The time to statistically significant reduction of the primary outcome (HF hospitalization and cardiovascular death) and its components, all-cause death, and HF death, were assessed in a post-hoc analysis of the SHIFT trial in the overall population (HR ≥70 bpm) and at HR ≥75 bpm, representing the approved label in many countries. Compared to placebo, the primary outcome and HF hospitalizations were significantly reduced at 102 days, while there was no effect on cardiovascular death, all-cause death, and HF death at HR ≥70 bpm. In the population with a baseline HR ≥75 bpm, a reduction of the primary outcome occurred after 67 days, HF hospitalization after 78 days, cardiovascular death after 169 days, death from HF after 157 days and all-cause death after 169 days. CONCLUSION: Treatment with ivabradine should not be deferred in patients in sinus rhythm with a HR of ≥70 bpm to reduce the primary outcome and HF hospitalizations, in particular in patients with HR ≥75 bpm. At HR ≥75 bpm, the time to risk reduction was shorter for reduction of hospitalization and mortality outcomes in patients with HFrEF after initiation of guideline-directed medication, including beta-blockers at maximally tolerated doses.

Comparison of Investigator-Reported and Centrally Adjudicated Heart Failure Outcomes in the EMPEROR-Reduced Trial.

BACKGROUND: There is limited published information on outcome adjudication in heart failure (HF). OBJECTIVES: The authors sought to compare investigator reports (IRs) to a Clinical Events Committee (CEC) and the impact of SCTI (Standardized Clinical Trial Initiative) criteria. METHODS: In the EMPEROR-Reduced trial, the authors compared IRs to the CEC for concordance; treatment effect on primary composite outcome events; and the components first event hospitalization primarily for HF or cardiovascular mortality (CVM), prognosis after hospitalization for heart failure (HHF), total HHFs, and trial duration with and without SCTI criteria. RESULTS: The CEC confirmed 76.3% of IR events for the primary outcome (CVM: 89.1%; HHF: 73.7%). The HR for treatment effect did not differ between adjudication methods for the primary outcome (IR: 0.75 [95% CI: 0.66-0.85]; CEC: 0.75 [95% CI: 0.65-0.86]), its components, or total HHFs. The prognosis after first HHF for all-cause mortality and CVM also did not differ between IR or CEC. Interestingly, IR primary HHF with different CEC primary cause had the highest subsequent fatal event rate. Full SCTI criteria were present in 90% of CEC HHFs-with a similar treatment effect to non-SCTI. The IR primary event reached the protocol target number (841) 3 months earlier than CEC (4 months with full SCTI criteria). CONCLUSIONS: Investigator adjudication is an alternative to a CEC with similar accuracy and faster event accumulation. The use of granular (SCTI) criteria did not improve trial performance. Finally, our data suggest that consideration be given to broadening the HHF definition to include "for or with" worsening disease. (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction [EMPEROR-Reduced]; NCT03057977).

Personalized care of patients with heart failure: are we ready for a REWOLUTION? Insights from two international surveys on healthcare professionals' needs and patients' perceptions.

AIMS: Guidelines for the management of heart failure (HF) are evolving, and increasing emphasis is placed on patient-centred care. As part of the REWOLUTION HF (REal WOrLd EdUcaTION in HF) programme, we conducted two international surveys aimed at assessing healthcare professionals' (HCPs) educational needs and patients' perspectives on the care of HF. METHODS AND RESULTS: Anonymous online questionnaires co-developed by HF experts and patients assessed HCPs' educational needs (520 respondents, mostly cardiologists, in 67 countries) and patients' perceptions on HF impact and management (98 respondents in 18 countries). Among HCPs, 62.7% prioritized rapid initiation of all guideline-mandated medications over up-titration of some medications, and 87.7% always or frequently discussed treatment goals with patients. There was good agreement between HCPs and patients on key treatment goals, except for a greater emphasis on reducing hospitalizations among HCPs. The most frequently cited barriers to the provision of guideline-recommended pharmacological therapy were treatment side effects/intolerance, complex treatment regimens, low blood pressure, cost/reimbursement issues, and low estimated glomerular filtration rate. Most patients (81.6%) reported no difficulties taking medications as prescribed, although 21.4% felt they were taking too many pills. Patients wanted more information about HF and its consequences, prognosis, and treatments (70.4%, 74.5% and 76.6%, respectively). Cardiologists were the preferred source of information about HF, followed by general practitioners and HF nurses. CONCLUSIONS: These surveys provide valuable insights into HCPs' needs about personalized care for patients with HF, as well as patients' perceptions, expectations and preferences. These findings will be helpful to develop patient-centred, needs-driven quality improvement programmes.

[Impact of Home Return Assistance Service in Heart Failure (PRADO-IC) on the one year re-hospitalisation and mortality in a heart failure hospitalized population of patients]. / Impact du programme d'aide au retour à domicile-insuffisance cardiaque (PRADO-IC) sur la mortalité et la réhospitalisation à un an dans une population de patients insuffisants cardiaques.

INTRODUCTION: Congestive heart failure (CHF) is associated with prolonged and recurrent hospitalizations; the prognosis remains poor. Since 2013, the Caisse Primaire d'Assurance Maladie (CPAM) has set up a support program PRADO-IC (support program for returning home after hospitalisation for heart failure). The aim of this study was to evaluate the impact of PRADO-IC on the heart failure readmission rate and death rate at one year. METHODS: From September 2016 to September 2018, all patients hospitalized for heart failure at Saint-Joseph Hospital were included in an observational study. The inclusion in PRADO-IC program was at physician's discretion. Two groups were compared according to the inclusion in PRADO-IC or not (T). The primary endpoints were the comparison of one-year mortality and heart failure readmission rate between the two groups. RESULTS: Six hundred and thirty-three patients were included, 262 in the PRADO-IC group and 371 in the non-PRADO group. Patients in the PRADO-IC cohort more frequently present severity criteria (age, weight, BNP level, arrhythmia, anemia, renal failure). Mortality at one year (19.5% vs 16.2%, p = 0.28) are equivalent in both groups. There were no significant differences in one-year rehospitalization rate for heart failure (HF) (35.1% in PRADO cohort vs 28% in T group, p = 0.06), the time to first hospitalization (74.5 days in PRADO vs 54.5 days in T, p = 0.55) and the length of hospitalization (6.0 days in PRADO vs 7.0 days in T, p = 0.29) between the two groups. Age, hyponatremia, anemia, cancer, HF re-hospitalization were variables linked to a risk of mortality, in a multivariable analysis. CONCLUSION: Our study shows that the PRADO-IC program concerned to the most severe patients. Despite this, the one-year mortality and the HF readmission rate are similar between the two groups.

Impact of chronic coronary syndromes on cardiovascular hospitalization and mortality: the ESC-EORP CICD-LT registry.

AIMS: In Europe, global data on guideline adherence, geographic variations, and determinants of clinical events in patients with chronic coronary syndrome (CCS) remain suboptimal. The European Society of Cardiology (ESC) EURObservational Research Programme (EORP) Chronic Ischemic Cardiovascular Disease Long-Term (CICD-LT) registry is a prospective European registry, and was designed to describe the profile, management, and outcomes of patients with CCS across the ESC countries. METHODS AND RESULTS: We aimed to investigate clinical events at 1-year follow-up from the ESC EORP CICD-LT registry.One-year outcomes of 6655 patients from the 9174 recruited in this European registry were analysed. Overall, 168 patients (2.5%) died, mostly from cardiovascular (CV) causes (n = 97, 1.5%). Northern Europe had the lowest CV mortality rate, while southern Europe had the highest (0.5 vs. 2.0%, P = 0.04). Women had a higher rate of CV mortality compared with men (2.0 vs. 1.3%, P = 0.02). During follow-up, 1606 patients (27.1%) were hospitalized at least once, predominantly for CV indications (n = 1220, 20.6%). Among the population with measured low-density lipoprotein-cholesterol level at 1 year, 1434 patients (66.5%) were above the recommended target. Age, history of atrial fibrillation, previous stroke, liver disease, chronic obstructive pulmonary disease or asthma, increased serum creatinine, and impaired left ventricular function were associated with an increased risk of CV death or hospitalization. CONCLUSION: In the CICD registry, the majority of patients with CCS have uncontrolled CV-risk factors. The 1-year mortality rate is low, but these patients are frequently hospitalized for CV causes. Early identification of comorbidities may represent an opportunity for enhanced care and better outcomes.

Données épidémiologiques d'une cohorte de patients hospitalisés pour insuffisance cardiaque. Étude mono-centrique sur 3 ans. Comparaison avec les données régionales.

INTRODUCTION: Congestiveheart failure (CHF) is associated with prolonged and recurrent hospitalizations, the prognosis remains poor. The aim of this study was to collect epidemiologic data at admission and at six month follow-up in a cohort of patients with CHF admitted to a single center between 2017 and 2019 (Saint Joseph Hospital, HSJ) and to compare these data with regional data (Ile-de-France, IdF). METHODS: Local and regional data were provided by National Health Service, Regional Department of Ile de France(DRSM) using national data base. CHF in-hospital stay was defined by appropriate CIM 10 code reported on the final medical form. RESULTS: From 2017 to 2019, 1967 CHF in-hospital stays were collected, mean age of the population was 81.4 (=mean) ± 11.7 yearsIC95% [80.8; 81.9], mean length of stay was 8.6 ± 6.8 days IC95% [8.3; 8.9], in-hospital mortality was 5.3 %, 9.6% at 2nd month and 15.9% at 6th month. Readmission rate was 23.7%, time to readmission was 59.5 ± 47.5 days IC95% [57.4; 61.6]. IdF data collected 60973 CHF in-hospital stays at the same period. Compared to the IdF population, our population was older (81.4 ± 11.6 versus 80.4 ± 12.6 years, p = 0.001). Length of stay was shorter (8.6 ± 6.8 versus 11.3 ± 10.1 days p<0.001), in-hospital mortality was lower (5.3% versus 7.8% p < 0.001), 2nd month and 6th month mortality was lower (respectively 9.6% versus 14.2% and 15.9% versus 21.3%, p <0.001), home discharge rate was higher (66.9% versus 60.8%, p < 0.001) in the HSJ population. The proportion of patients included in PRADO-IC program (Programme d'aide au retour à domicile-Insuffisance Cardiaque, Returning home support program) was higher in SJ population (22.6% versus 8.8% p < 0.001). CONCLUSION: CHF admission involved elderly patients, the in-hospital and 6th month mortality is high, with early and frequent readmissions. Differences between HSJ and IdF populations may be explained by the heterogeneity of health care facilities, management facilities and organization of transition of care.

Effect of Empagliflozin on Worsening Heart Failure Events in Patients With Heart Failure and Preserved Ejection Fraction: EMPEROR-Preserved Trial.

BACKGROUND: Empagliflozin reduces the risk of cardiovascular death or hospitalization for heart failure in patients with heart failure with preserved ejection fraction, but additional data are needed about its effect on inpatient and outpatient heart failure events. METHODS: We randomly assigned 5988 patients with class II through IV heart failure with an ejection fraction of >40% to double-blind treatment with placebo or empagliflozin (10 mg once daily), in addition to usual therapy, for a median of 26 months. We prospectively collected information on inpatient and outpatient events reflecting worsening heart failure and prespecified their analysis in individual and composite end points. RESULTS: Empagliflozin reduced the combined risk of cardiovascular death, hospitalization for heart failure, or an emergency or urgent heart failure visit requiring intravenous treatment (432 versus 546 patients [empagliflozin versus placebo, respectively]; hazard ratio, 0.77 [95% CI, 0.67-0.87]; P<0.0001). This benefit reached statistical significance at 18 days after randomization. Empagliflozin reduced the total number of heart failure hospitalizations that required intensive care (hazard ratio, 0.71 [95% CI, 0.52-0.96]; P=0.028) and the total number of all hospitalizations that required a vasopressor or positive inotropic drug (hazard ratio, 0.73 [95% CI, 0.55-0.97]; P=0.033). Compared with patients in the placebo group, fewer patients in the empagliflozin group reported outpatient intensification of diuretics (482 versus 610; hazard ratio, 0.76 [95% CI, 0.67-0.86]; P<0.0001), and patients assigned to empagliflozin were 20% to 50% more likely to have a better New York Heart Association functional class, with significant effects at 12 weeks that were maintained for at least 2 years. The benefit on total heart failure hospitalizations was similar in patients with an ejection fraction of >40% to <50% and 50% to <60%, but was attenuated at higher ejection fractions. CONCLUSIONS: In patients with heart failure with preserved ejection fraction, empagliflozin produced a meaningful, early, and sustained reduction in the risk and severity of a broad range of inpatient and outpatient worsening heart failure events. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03057977.

Aging increases circulating BH2 without modifying BH4 levels and impairs peripheral vascular function in healthy adults.

Little is known about the mechanisms of aging on vascular beds and its relationship with tetra and di-hydrobiopterin (BH4 and BH2) levels. This observational clinical study analyzed the impact of aging on plasma and platelet biopterins, cutaneous blood flow (CBF), and coronary flow reserve (CFR) in healthy adults. The study enrolled healthy adults in 3 age groups: 18-30, 50-59, and 60-70 years (n = 25/group). Biopterins were assessed by LC-MS/MS using newly defined pre-analytical conditions limiting BH4 oxidation and improving long-term stability. CBF was measured by Laser Speckle Contrast Imaging coupled with acetylcholine-iontophoresis and CFR by adenosine stress cardiac magnetic resonance. In healthy adults, aging (60-70 years vs 18-30 years) significantly increased platelet BH2 (+75%, P = 0.033) and BH2 + BH4 (+31%, P = 0.033), and to a lesser extent plasma BH2 (+29%, P = 0.009) without affecting BH4 and BH4/BH2. Simultaneously, CBF was decreased (-23%, P = 0.004) but not CFR, CBF being inversely correlated with platelet BH2 (r = -0.42, P = 0.001) and BH2 + BH4 (r = -0.41, P = 0.002). The proportion of adults with abnormal platelet BH2 increased with age (+28% in 60-70y). These abnormal BH2 levels were significantly associated with reduced CBF and CFR (-16%, P = 0.03 and -26%, P = 0.02). In conclusion, our study showed that age-related peripheral endothelial dysfunction was associated with an increase in circulating BH2 without decreasing BH4, the effect being more marked in platelets, the most relevant blood compartment to assess biopterin bioavailability. Peripheral but not coronary vascular function is progressively impaired with aging in healthy adults. All these findings support biopterins as therapeutic targets to improve vascular function.

Effect of Sotagliflozin on Total Hospitalizations in Patients With Type 2 Diabetes and Worsening Heart Failure : A Randomized Trial.

BACKGROUND: In the SOLOIST-WHF (Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post Worsening Heart Failure) trial, sotagliflozin, a sodium-glucose cotransporter-1 and sodium-glucose cotransporter-2 inhibitor, reduced total occurrences of cardiovascular deaths, hospitalizations for heart failure, and urgent visits for heart failure relative to placebo by 33%. OBJECTIVE: To determine whether sotagliflozin increased the prespecified efficacy outcome of days alive and out of the hospital (DAOH) in the SOLOIST-WHF trial. DESIGN: Randomized, double-blind, placebo-controlled trial. (ClinicalTrials.gov: NCT03521934). SETTING: 306 sites in 32 countries. PARTICIPANTS: 1222 patients with type 2 diabetes and reduced or preserved ejection fraction who were recently hospitalized for worsening heart failure. INTERVENTION: 200 mg of sotagliflozin once daily (with a possible dose increase to 400 mg) or matching placebo. MEASUREMENTS: The primary analysis included hospitalizations for any reason on the basis of investigator-reported incidence and duration of admissions after randomization. Days alive and out of the hospital and its converse (days dead and days in the hospital) were analyzed using prespecified Poisson regression models. RESULTS: Although similar proportions of patients in the sotagliflozin and placebo groups were hospitalized at least once (38.5% vs. 41.4%), fewer patients in the sotagliflozin group were hospitalized more than once (16.3% vs. 22.1%). There were 64 and 76 deaths in the sotagliflozin and placebo groups, respectively. The DAOH rate in the sotagliflozin group was 3% higher than in the placebo group (rate ratio [RR], 1.03 [95% CI, 1.00 to 1.06]; P = 0.027). This difference was primarily driven by a reduction in the rate of days dead (RR, 0.71 [CI, 0.52 to 0.99]; P = 0.041) rather than by a reduction in the rate of days hospitalized for any cause. For every 100 days of follow-up, patients in the sotagliflozin group were alive and out of the hospital for 3% or 2.9 more days than those in the placebo group (91.8 vs. 88.9 days); this difference reflected a 2.6-day difference in days dead (6.3 vs. 8.9 days) and a 0.3-day difference in days in the hospital (1.9 vs. 2.2 days). LIMITATION: Other than heart failure, the primary reason for each hospitalization was unspecified. CONCLUSION: Sotagliflozin increased DAOH, a metric that may provide an additional patient-centered outcome to capture the totality of disease burden. Future studies are needed to quantify the consequences of increasing DAOH in terms of health economics and patient quality of life. PRIMARY FUNDING SOURCE: Sanofi at initiation and Lexicon Pharmaceuticals at completion.

Profile and treatment of chronic coronary syndromes in European Society of Cardiology member countries: The ESC EORP CICD-LT registry.

BACKGROUND: International guidelines recommend pharmacotherapy combinations for chronic coronary syndromes (CCSs) but medical management remains suboptimal. DESIGN: The CICD-LT registry is investigating short- and long-term outcomes and management in patients in European Society of Cardiology (ESC) member countries, in a longitudinal ESC EURObservational Research Programme aimed at improving CCS management. METHODS: Between 1 May 2015 and 31 July 2018, 9174 patients with previous ST-elevation myocardial infarction (STEMI), non-STEMI or coronary revascularisation, or other CCS, were recruited during a routine ambulatory visit or elective revascularisation procedure. Baseline clinical data were recorded and prescribed medications analysed at initial contact and discharge, and according to patient gender and age (<75 vs. ≥75 years). RESULTS: Poorly controlled cardiovascular risk factors, including current smoking (18.5%), obesity (33.9%), diabetes (25.8%), raised low-density lipoprotein cholesterol (73.3%) and persistent hypertension (24.7%), were common across all cohorts. At ambulatory visit or admission, the guidelines-recommended combination of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, beta-blocker, aspirin, statin and any antiplatelet agent was prescribed to 57.8% of patients with STEMI/NSTEMI. Differences in prescribing rates, including for combination therapies, were observed based on age and gender and persisted after adjustment for demographic factors. CONCLUSIONS: Cardiovascular risk factors were common in contemporary CCS patients and secondary prevention prescribing was suboptimal. Patients aged ≥75 years and, to some extent, female patients were less likely to receive guidelines-recommended drug combinations than younger and male patients. One- and two-year follow-up will study prescribing changes and associations between baseline characteristics/prescribing and subsequent clinical outcomes.

Patient factors associated with titration of medical therapy in patients with heart failure with reduced ejection fraction: data from the QUALIFY international registry.

AIMS: Failure to prescribe key medicines at evidence-based doses is associated with increased mortality and hospitalization for patients with Heart Failure with reduced Ejection Fraction (HFrEF). We assessed titration patterns of guideline-recommended HFrEF medicines internationally and explored associations with patient characteristics in the global, prospective, observational, longitudinal registry. METHODS AND RESULTS: Data were collected from September 2013 through December 2014, with 7095 patients from 36 countries [>18 years, previous HF hospitalization within 1-15 months, left ventricular ejection fraction (LVEF) ≤ 40%] enrolled, with dosage data at baseline and up to 18 months from 4368 patients. In 4368 patients (mean age 63 ± 17 years, 75% male) ≥ 100% target doses at baseline: 30.6% (ACEIs), 2.9% (ARBs), 13.9% (BBs), 53.8% (MRAs), 26.2% (ivabradine). At final follow-up, ≥100% target doses achieved in more patients for ACEI (34.8%), BB (18.0%), and ivabradine (30.5%) but unchanged for ARBs (3.2%) and MRAs (53.7%). Adjusting for baseline dosage, uptitration during follow-up was more likely with younger age, higher systolic blood pressure, and in absence of chronic kidney disease or diabetes for ACEIs/ARBs; younger age, higher body mass index, higher heart rate, lower LVEF, and absence of coronary artery disease for BBs. For ivabradine, uptitration was more likely with higher resting heart rate. CONCLUSIONS: The international QUALIFY Registry suggests that few patients with HFrEF achieve target doses of disease-modifying medication, especially older patients and those with co-morbidity. Quality improvement initiatives are urgently required.

The Impact of Patients With Cardiac Amyloidosis in HFpEF Trials.

Heart failure with preserved ejection fraction (HFpEF) is an increasingly diagnosed condition whose failure to respond to new drugs effective in heart failure with reduced ejection fraction is of great concern. HFpEF is an incompletely understood and markedly heterogeneous syndrome, but cardiac amyloidosis is increasingly recognized as one of its various causes. The specific hemodynamic and pathophysiological features of cardiac amyloidosis result in poor tolerance of heart failure medications and in worse outcomes compared with other causes. Until recently, patients considered for HFpEF trials were not routinely screened for cardiac amyloidosis. This review examines how real-world patients with cardiac amyloidosis met inclusion criteria for 8 major HFpEF clinical trials, including the recent PARAGON (Prospective Comparison of ARNI with ARB Global Outcomes in HF With Preserved Ejection Fraction) trial. This review discusses how the presence in the trial populations of a subset of patients with cardiac amyloidosis might contribute to explain the absence of efficacy of medications for HFpEF in trials so far. A multistep screening strategy is suggested in which patients with red flags for cardiac amyloidosis undergo both a light chain assay and technetium-labeled cardiac scintigraphy (technetium-labeled cardiac scintigraphy scan), which, when negative, rule out cardiac amyloidosis. Using this strategy would allow the testing of new medications for HFpEF in populations containing no patients with cardiac amyloidosis, thus potentially increasing the likelihood of showing therapeutic efficacy, and finally making some effective treatment available.

Effect of Empagliflozin on the Clinical Stability of Patients With Heart Failure and a Reduced Ejection Fraction: The EMPEROR-Reduced Trial.

BACKGROUND: Empagliflozin reduces the risk of cardiovascular death or hospitalization for heart failure in patients with heart failure and a reduced ejection fraction, with or without diabetes, but additional data are needed about the effect of the drug on inpatient and outpatient events that reflect worsening heart failure. METHODS: We randomly assigned 3730 patients with class II to IV heart failure with an ejection fraction of ≤40% to double-blind treatment with placebo or empagliflozin (10 mg once daily), in addition to recommended treatments for heart failure, for a median of 16 months. We prospectively collected information on inpatient and outpatient events reflecting worsening heart failure and prespecified their analysis in individual and composite end points. RESULTS: Empagliflozin reduced the combined risk of death, hospitalization for heart failure or an emergent/urgent heart failure visit requiring intravenous treatment (415 versus 519 patients; empagliflozin versus placebo, respectively; hazard ratio [HR], 0.76; 95% CI, 0.67-0.87; P<0.0001). This benefit reached statistical significance at 12 days after randomization. Empagliflozin reduced the total number of heart failure hospitalizations that required intensive care (HR, 0.67; 95% CI, 0.50-0.90; P=0.008) and that required a vasopressor or positive inotropic drug or mechanical or surgical intervention (HR, 0.64; 95% CI, 0.47-0.87; P=0.005). As compared with placebo, fewer patients in the empagliflozin group reported intensification of diuretics (297 versus 414 [HR, 0.67; 95% CI, 0.56-0.78; P<0.0001]). Additionally, patients assigned to empagliflozin were 20% to 40% more likely to experience an improvement in New York Heart Association functional class and were 20% to 40% less likely to experience worsening of New York Heart Association functional class, with statistically significant effects that were apparent 28 days after randomization and maintained during long-term follow-up. The risk of any inpatient or outpatient worsening heart failure event in the placebo group was high (48.1 per 100 patient-years of follow-up), and it was reduced by empagliflozin (HR, 0.70; 95% CI, 0.63-0.78; P<0.0001). CONCLUSIONS: In patients with heart failure and a reduced ejection fraction, empagliflozin reduced the risk and total number of inpatient and outpatient worsening heart failure events, with benefits seen early after initiation of treatment and sustained for the duration of double-blind therapy. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03057977.

Asymptomatic left ventricular dysfunction in patients with type 2 diabetes free of cardiovascular disease and its relationship with clinical characteristics: The DIACAR cohort study.

AIMS: To assess the prevalence, type and clinical factors associated with left ventricular (LV) dysfunction in patients with type 2 diabetes mellitus (T2DM) by performing a comprehensive echocardiographic Doppler assessment including speckle tracking. METHODS: Two hundred T2DM patients without overt cardiovascular disease were prospectively enrolled in a single-centre cohort study between 2018 and 2019. RESULTS: Left ventricular mass was increased in 24 patients (12%) and relative wall thickness (h/r) was increased in 46 patients (23%). Left atrial (LA) enlargement was observed in 27 patients (13.6%) and global longitudinal strain (GLS) was reduced in 38 patients (20.3%). In univariate analysis, LV hypertrophy (LVH) or increased h/r were associated with age, renal function, hypertension and B-type natriuretic peptide (BNP) plasma level. LA dilation was associated with age, history of hypertension, diabetes duration and complications, insulin treatment, BNP level and renal function. GLS was associated with body mass index (BMI) and, in a borderline manner, with diabetes duration. In multivariate analysis, hypertension was associated with LVH and with h/r and a borderline relationship was observed for female gender (LVH), age and insulin treatment (h/r). Age, hypertension and, in a borderline manner, insulin treatment were associated with LA dilation. BMI and shorter diabetes duration were associated with reduced GLS. CONCLUSION: A high prevalence of asymptomatic cardiac dysfunction/structural abnormalities was observed in patients with T2DM without overt cardiac disease and was associated with either age, diabetes duration or treatment and with comorbidities including hypertension and obesity. Whether these preclinical abnormalities are associated with poor outcomes warrants further study.

The ESC-EORP Chronic Ischaemic Cardiovascular Disease Long Term (CICD LT) registry.

AIMS: The European Society of Cardiology (ESC) EURObservational Research Programme (EORP) Chronic Ischaemic Cardiovascular Disease Long Term (CICD LT) registry aims to study the clinical profile, treatment modalities, and outcomes of patients diagnosed with CICD in a contemporary environment in order to assess whether these patients at high cardiovascular (CV) risk are treated according to ESC guidelines on prevention or on stable coronary disease and to determine mid- and long-term outcomes and their determinants in this population. METHODS AND RESULTS: Nine thousand one hundred and seventy-four patients over 18 years with documented CICD defined by a history acute coronary syndrome with/without ST elevation, previous coronary revascularization, or stable coronary artery disease were enrolled between 1 May 2015 and 31 July 2018. Individual patient data on clinical profile, biology, and treatment modalities were collected across 154 centres from 20 ESC countries. Two years of follow-up is scheduled in order to determine the following clinical outcomes: all-cause and CV death, all-cause and CV hospitalizations, changes in medications, and quality of life using the EuroQol5D-5L score. CONCLUSION: The CICD LT is an international registry of care and outcomes of patients hospitalized with CICD which will provide insights into the contemporary profile and management of patients with this common disease.