Composite Of Heart Failure Hospitalization Research Articles

Body mass index and clinical outcomes in patients with diabetes and stable coronary artery disease in THEMIS

Abstract Background Physiologic changes due to extremes of body weight may affect the efficacy and tolerability of antiplatelet treatment. However, it remains unclear whether the risks and benefits of intensified antiplatelet therapy among patients with diabetes and stable coronary artery disease (CAD) are affected by body mass index (BMI). Purpose To assess the relationship between baseline BMI and major adverse cardiovascular (CV) events, and to determine if the effects of ticagrelor vs. placebo varied across the BMI spectrum, in patients with diabetes and stable CAD. Methods THEMIS was a randomized, controlled trial of 19,220 individuals aged ≥50 years with type 2 diabetes and stable CAD, randomly allocated to ticagrelor or placebo on top of aspirin. Patients with a prior myocardial infarction (MI) or stroke, or already on dual antiplatelet therapy, were excluded. The primary efficacy outcome was a composite of CV death, MI, or stroke. The primary safety outcome was TIMI major bleeding. We examined prognostic implications of BMI using 1) restricted cubic splines for the overall trends with outcomes; 2) Cox regression models with predefined BMI intervals (<25 kg/m2, 25-29.9 kg/m2, and ≥30 kg/m2) adjusted for demographic, clinical, and laboratory variables; and 3) Cox regression models for the effects of ticagrelor vs. placebo on outcomes across the spectrum of BMI values (test for interaction). A two-sided P-value <0.01 was considered statistically significant to control the overall chance of type I errors. Results BMI was available in 19,202 (99.9%) participants, with a median of 29 kg/m2 (interquartile range: 26-33). A total of 3352 (17.5%) individuals had a BMI <25 kg/m2, 7644 (39.8%) had a BMI 25-29.9 kg/m2, and 8206 (42.7%) had a BMI ≥30 kg/m2. Median follow-up was 39.9 months (range 0-57), with 1554 primary efficacy events and 306 primary safety events occurring over the course of the study. BMI was not associated with the primary efficacy or safety outcome, or with their individual components. However, BMI was significantly associated with hospitalization for heart failure (HHF) (BMI <25 kg/m2: reference; hazard ratio [HR] for BMI 25-29.9 kg/m2: 1.07, 95% confidence interval [CI], 0.82 to 1.40; HR for BMI ≥30 kg/m2: 1.41, 95% CI, 1.07 to 1.84) and with the composite of HHF or CV death (comparable estimates) after multivariable adjustment (Figure). BMI was also significantly, positively associated with serious adverse events (BMI <25 kg/m2: reference; HR for BMI 25-29.9 kg/m2: 0.99, 95% CI, 0.93 to 1.06; HR for BMI ≥30 kg/m2: 1.20, 95% CI, 1.12 to 1.29). BMI did not modify the risks and benefits of ticagrelor vs. placebo. Conclusions BMI was independently associated with the risk of HHF and the composite of HHF or CV death, but not with other efficacy or safety outcomes, in patients with stable CAD and type 2 diabetes. Ticagrelor was of similar benefit on the primary efficacy outcome vs. placebo across the full range of BMI.

Different right ventricular mechanics in atrial and ventricular secondary tricuspid regurgitation and their prognostic role. A multicentric three-dimensional echocardiography study

Abstract Background/Introduction Secondary tricuspid regurgitation (STR) can develop from markedly different etiologies. Both progressive dilation and dysfunction of the right atrium (atrial phenotype, ASTR), and adverse right ventricular (RV) remodeling (ventricular phenotype, VSTR) may result in STR. RV function is a major determinant of outcome in patients with STR. However, data about how RV function adapts to ASTR and VSTR are scarce, and the prognostic implications of RV mechanics in ASTR and VSTR remain to be clarified. Purpose Accordingly, we aimed to investigate the RV mechanical patterns in ASTR and VSTR and to examine their prognostic role using three-dimensional (3D) echocardiography. Methods We enrolled 192 patients with STR (60% women) who underwent clinically indicated transthoracic echocardiography in a multicentric prospective observational study. The primary outcome was defined as a composite of heart failure hospitalization or cardiac death. STR etiology was assessed based on the TVARC criteria (ventricular STR n=134, atrial STR n=58). STR severity was categorized using STR effective regurgitant orifice area according to current guidelines. We assessed RV function by measuring the tricuspid annular plane systolic excursion (TAPSE) by M-mode echocardiography and RV ejection fraction (EF) by 3D echocardiography. In addition, we imported the 3D RV meshes into the ReVISION software package (Argus Cognitive, Inc, Lebanon, USA) to quantify the relative contribution of the longitudinal (LEFi), radial (REFi), and anteroposterior motion components (AEFi) to total RV EF. Results ASTR and VSTR patients had comparable TAPSE (17±5 mm vs. 18±5 mm, p=0.10), while RV EF was significantly higher in ASTR (54±7% vs. 47±10% p<0.001). Although LEFi (0.37±0.08 vs. 0.38±0.10, p=0.95) and AEFi (0.45±0.08 vs. 0.44±0.11, p=0.53) were comparable between ASTR and VSTR, REFi was significantly lower in VSTR (0.52±0.09 vs. 0.47±0.12, p<0.01). RF EF was comparable among STR severity grades (mild vs. moderate vs. severe: 50±11 vs. 49±9 vs. 50±10%, respectively, p=0.85). Conversely, LEFi was significantly higher in mild and moderate STR vs severe STR (0.39±0.08 vs. 0.39±0.09 vs. 0.35±0.10, respectively, p=0.04). Using multivariable Cox regression based on variables significant in the univariate analysis, REFi was a significant independent predictor of outcome in the entire cohort (hazard ratio: 0.978 [CI, 0.959-0.999], p= 0.037). Conclusions Using 3D echocardiographic assessment, ASTR and VSTR patients demonstrated significant differences in the RV mechanical pattern, with a lower contribution of the radial contraction in the case of ventricular STR etiology. While RV EF was comparable between STR severity grades, the relative importance of the longitudinal motion significantly differed. Notably, the relative contribution of radial motion to RV function demonstrated independent prognostic value in patients with STR.RV mechanics in STR severity stages

Disparities in clinical characteristics, treatment, and prognosis among immigrants and native patients in Denmark with new-onset heart failure and reduced ejection fraction

Abstract Background Major variations exist in the causes, age at diagnosis, and outcomes of heart failure (HF) in patients from different parts of the world. Purpose To elucidate this issue further, we compared the characteristics and outcomes of immigrants living in Denmark and native Danish patients presenting with new-onset HF with reduced ejection fraction (HFrEF). Methods By linkage of the Danish Heart Failure Registry, and nationwide administrative registries, we identified patients with new onset HFrEF, from 2005-2021, grouped according to immigration status and, if not native Danish, region of origin, according to the World Bank classification. Outcomes were a 1) composite of HF hospitalization or all-cause death at 3 years follow-up, and 2) initiation and up-titration of guidelines-directed medical therapy (GDMT) at 12 months follow-up. Cox regression analyses adjusted for age, sex, calendar year, HF severity, socioeconomic status, and major comorbidities were used to compare the primary composite outcome. Results Of 33,297 patients included, 31,602 (97.9%) were native Danish patients (DK), 1031 (3.1%) were originally from Europe/Central Asia (EUR/CA), 439 (1.3%) from Middle East/North Africa (ME/NAF), 225 (0.7%) from South Asia (SA). The median time since immigration ranged from 20 to 30 years. Compared to DK, patients originating from ME/NAF, and SA were around 10 years younger (median age 62-64 vs. 71 years), had similar median left ventricular ejection fraction (30% vs. 30%), had lower New York Heart Association (NYHA) ≥ class III (14-16% vs. 23%), had more diabetes (39-51% vs. 20%) and ischemic heart disease (IHD) (69-75 vs. 48%), and had less atrial fibrillation (AF) (9-14% vs. 32%) (all p < 0.0001), patients from EUR/CA were generally similar to DK. The crude 3-year cumulative risk of the primary composite outcome was 34% (DK), 31% (EUR/CA), 27% (SA), and 23% (ME/NAF) (Figure 1) In adjusted analyses with DK as the reference, only ME/NAF was associated with a lower risk; hazard ratio (HR) 0.77 (95% confidence interval (CI) 0.62-0.94) (Figure 2). No major differences in the initiation and up-titration of GDMT were observed across groups. Conclusions Non-Western immigrants living in Denmark who presented with new-onset HFrEF had a distinct clinical profile, being generally younger, had lower NYHA class but similar LVEF, a greater prevalence of diabetes and IHD and less AF compared to native Danish patients. In addition, they had lower adjusted rates of the primary outcome of HF hospitalization or all-cause death and a similar likelihood of GDMT initiation and up-titration. The reasons for these differences deserve more research.Figure 1 Crude cumulative riskFigure 2 Adjusted rates

Clinical correlates and prognostic impact of cognitive decline in patients with heart failure and preserved ejection fraction: insights from PARAGON-HF

Abstract Background Cognitive decline is common in patients with heart failure (HF), but its clinical correlates and prognostic impact are not well understood in this population. Purpose To examine the baseline variables associated with cognitive decline and the associations between cognitive decline and HF outcomes in patients with heart failure and preserved ejection fraction (HFpEF). Methods We analyzed cognitive function, as measured by the Mini-Mental State Examination (MMSE), in 2895 patients with HFpEF enrolled in a pre-specified sub-study of PARAGON-HF. Logistic regression analysis was performed to determine the factors associated with cognitive decline i.e., a decrease in MMSE score of ≥3 points by 48 weeks. Time-updated Cox proportional hazards regressions and semiparametric proportional rates models were used to examine the subsequent risk of clinical outcomes after a decline in MMSE scores of ≥1-, 2- and 3-points during follow-up respectively, adjusted for known prognostic variables including NT-proBNP and baseline MMSE. Results A total of 450 (15.5% of the population) patients experienced a decrease in MMSE score of ≥3 points from baseline, at any follow-up visit. The corresponding number for a decrease in MMSE score of ≥2 points and ≥1 point was 755 (26.1%) and 1231 (42.5%), respectively. Independent predictors of cognitive decline at 48 weeks included older age, living in Latin America or the Asia/Pacific region, ischemic etiology, prior HF hospitalization, history of stroke/TIA, and lower serum albumin level (Figure 1). There was a graded relationship between the size of the decrease in MMSE score from baseline and the subsequent risk of mortality. Notably, a decrease of ≥3 points was associated with a 50% increase in the subsequent risk of death from any cause (adjusted HR 1.53, 95% CI 1.10-2.11) and a 90% elevation in risk of death from cardiovascular causes (1.89, 1.25-2.86), respectively, after extensive adjustment for known prognostic variables and baseline MMSE score. By contrast, cognitive decline during follow-up was not associated with a higher risk of HF hospitalization or the composite of HF hospitalization or CV death (Figure 2). Conclusions In patients with HFpEF, a decline in MMSE score during follow-up is independently associated with a graded increase in the risk for mortality, but not of HF hospitalization.The predictors for cognitive declineRisk of outcomes after a decline in MMSE

Improving the prediction of major adverse cardiovascular events in patients with hypertrophic cardiomyopathy by adding plasma SVEP1 to conventional clinical model including NT-proBNP

Abstract Background Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disease with a prevalence between 1 in 200 to 500 [1]. HCM can lead to major adverse cardiovascular events (MACE) such as heart failure (HF) hospitalization and cardiac death [2,3]. A protein named "sushi, von Willebrand factor type A, EGF and pentraxin domain containing 1" (SVEP1) is a large extracellular matrix protein whose activity can be measured in plasma [4,5]. SVEP1 promotes inflammation and atherosclerosis [4,5]. SVEP1 is associated with risk of HF hospitalization and cardiac death in patients with HF with reduced ejection fraction [6]. However, no prior study has assessed the prognostic value of SVEP1 in patients with HCM. Purpose To test the hypothesis that the addition of SVEP1 improves the predictive performance of the conventional model based on clinical risk factors plus NT-proBNP for future MACE in patients with HCM. Methods We performed a multicenter prospective cohort study of patients with HCM [7]. The outcome was MACE, defined as a composite of HF hospitalization or cardiac death [6]. After dividing the cohort into four groups using the median values of SVEP1 and NT-proBNP, we compared the risk of the outcome event using the Cox proportional hazards model adjusting for 15 clinical risk factors known to be associated with MACE in HCM (Figure 1) [8-11]. We also developed the Lasso-regularized Cox proportional hazards model to predict the time to first MACE by adding SVEP1 to the 15 clinical risk factors with or without NT-proBNP in the training cohort (randomly selected 75% of the cohort). We then compared the predictive performance in the test cohort (25% of the cohort) using the C-statistic of each model. Results During a median follow-up of 1.9 (25 percentile-75 percentile, 0.7-4.3) years, the outcome event occurred in 63 (10%) of 610 patients. The four groups stratified by the median of SVEP1 and NT-proBNP levels had different risks of the outcome event (log-rank p<0.001: Figure 1). Even in the groups with lower-than-median NT-proBNP levels, the high-SVEP1 group had higher risks of MACE compared with the low-SVEP1 group (adjusted hazard ratio 4.52, p=0.042: Figure 1). In the prediction of time to first MACE, the addition of SVEP1 improved the C-statistic of the clinical model (p<0.001) and that of the clinical plus NT-proBNP model (p=0.01: Figure 2). The clinical plus SVEP1 model also outperformed the clinical plus NT-proBNP model (p=0.005: Figure 2). Conclusions In the present multicenter prospective cohort study of 610 patients with HCM, SVEP1 improved MACE risk stratification when added to the conventional model consisting of clinical risk factors plus NT-proBNP. SVEP1 also exhibited a superior predictive ability than NT-proBNP to predict MACE in patients with HCM. These data collectively indicate that SVEP1 provides additional risk stratification and may be a better biomarker than NT-proBNP for the prognostication of patients with HCM.Figure 1.Kaplan-Meier curves for MACEFigure 2.Time-dependent AUROC curves

Ferritin, inflammation, and iron deficiency in acute heart failure: evidence from the EDIFICA cohort

Abstract Background Ferritin is commonly used to evaluate iron stores and guide therapeutic decisions regarding intravenous iron supplementation. However, in the context of AHF, inflammation-driven upregulation of ferritin might disrupt its correlation with iron stores, restricting iron bioavailability and potentially amplifying the inflammatory response. Aim This study aims to assess the clinical and prognostic associations of ferritin levels in an AHF cohort and to determine whether the prognostic value of ferritin is influenced by the presence of infection, inflammatory activation, and other markers of iron deficiency. Methods The association between ferritin and clinical outcomes (180 days) in AHF was evaluated in a cohort of 526 patients from the EDIFICA registry. Results The median ferritin plasma concentration at admission was 180 pg/mL. Patients with higher ferritin levels at admission were predominantly men, exhibiting a high prevalence of chronic kidney disease and alcohol consumption, and presenting with lower blood pressure and a higher incidence of clinical infection. Higher ferritin levels were associated with increased risk of the composite of heart failure hospitalization or cardiovascular death (Tertile 2: HR 1.75; 95% CI 1.10–2.79; p = 0.017; Tertile 3: HR 1.79; 95% CI 1.08–2.97; p = 0.025), independently of classical HF prognostic factors, inflammatory and iron-related markers. No significant associations were found between admission serum iron or transferrin saturation tertiles, iron status categories, or guideline-defined iron deficiency (ID) criteria and the primary composite outcome. However, at discharge, patients who met the criteria for defective iron utilization, low iron storage, or guideline-defined ID had a lower risk of the composite endpoint compared to those with normal iron utilization or who did not meet the guideline-defined ID criteria, respectively. Conclusions Elevated ferritin levels are independently associated with poor prognosis in AHF. Low ferritin levels are associated with a favorable outcome and do not carry significant value in identifying ID in this population.

Prognostic significance of ratio of P-wave duration to P-wave vector magnitude for mortality in acute anterior myocardial infarction

BackgroundThe impact of P-wave abnormality in acute anterior MI, where the culprit vessel is the left anterior descending artery, remains undetermined. This study aimed to elucidate the impact of P-wave morphology on clinical outcomes in acute anterior MI. MethodsPatients undergoing emergent percutaneous coronary intervention for acute anterior MI were enrolled between September 2014 and April 2019 (derivation cohort) and May 2019 through July 2023 (validation cohort). P-wave duration (Pd) and P-wave vector magnitude (Pvm) were measured. The Pvm was calculated as the square root of the sum of the squared P-wave magnitudes in leads II and V6 and one-half of the P-wave amplitude in V2. The patients were categorized into high and low Pd/Pvm groups using a statistically derived cut-off value. The endpoint comprised the composite of heart failure (HF) hospitalization and all-cause death. ResultsConsecutive 426 patients were enrolled in this study (derivation cohort, 213 patients; validation cohort, 216 patients). The calculated cut-off value of Pd/Pvm for predicting the clinical endpoint, determined through receiver operating curve analysis, was 793.5 ms/mV (area under the curve [AUC] = 0.85, sensitivity of 73.8 %, and specificity of 94.0 %) in the derivation cohort. Kaplan-Meier analyses revealed a significantly higher risk of the endpoint in patients with high Pd/Pvm than those with low Pd/Pvm in derivation and validation cohorts (Log-rank p < 0.001 and p < 0.001, respectively). Multivariate Cox proportional hazards analysis identified advanced age, elevated Pd/Pvm, and reduced left ventricular ejection fraction as independent and significant factors associated with the endpoint in the validation cohort (p = 0.008, p < 0.001, and p < 0.001, respectively). ConclusionHigh Pd/Pvm was significantly associated with the composite of HF hospitalization and all-cause death after acute anterior MI.

ST-segment depression and left ventricular systolic function recovery post-atrial fibrillation ablation in heart failure.

Catheter ablation (CA) of atrial fibrillation (AF) improves left ventricular ejection fraction (LVEF) in patients with heart failure with reduced ejection fraction (HFrEF). The impact of ST-segment depression before CA on LVEF recovery and clinical outcomes remains unknown. In the present study, we aimed to investigate the relationship between ST-segment depression during AF rhythm before CA and improvement in the LVEF and clinical outcomes in persistent atrial fibrillation (PerAF) patients with HFrEF. The present study included 122 PerAF patients (male; 98 patients, 80%, mean age: 69 [56, 76] years) from the Osaka Rosai Atrial Fibrillation ablation (ORAF) registry who had LVEF<50% and underwent an initial ablation. The patients who underwent percutaneous coronary intervention or coronary artery bypass grafting within the past 1month were not included in the enrolled patients. We assigned the patients based on the presence of ST-segment depression before CA during AF rhythm and evaluated improvement in the LVEF (LVEF≥15%) 1year after CA and the relationship between ST-segment depression and heart failure (HF) hospitalization/major adverse cardiovascular events (MACE), which are defined as a composite of HF hospitalization, cardiovascular death, hospitalization due to coronary artery disease, ventricular arrhythmia requiring hospitalization and stroke. The percentage of patients with improvement in the LVEF 1year after CA was significantly lower in the patients with ST-segment depression than those without (58.6% vs. 79.7%, P=0.012). Multiple regression analysis showed ST-segment depression was independently and significantly associated with improvement in the LVEF 1year after CA (HR: 0.35; 95% CI: 0.129-0.928, P=0.035). Kaplan-Meier analysis showed that the patients with ST-segment depression significantly had higher risk of HF hospitalization and MACE than those without (log rank P=0.022 and log rank P=0.002, respectively). Multivariable Cox proportional hazards analysis showed that ST-segment depression was independently and significantly associated with a higher risk of MACE (HR: 2.82; 95% CI: 1.210-6.584, P=0.016). ST-segment depression before CA during AF rhythm was useful prognostic predictor of improvement in the LVEF and clinical outcomes including HF hospitalization and MACE in PerAF patients with HFrEF.

Premature Acute Myocardial Infarction Treated With Invasive Revascularization: Comparing STEMI With NSTEMI in a Population-Based Study of Young Patients

BackgroundAcute myocardial infarction (AMI) usually presents in older populations, in which there are established demographic and outcome differences for ST-elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI). No similar comparisons for AMI in the young population exist. MethodsWe compared all index NSTEMI and STEMI hospitalizations in young (18-45 years) patients who required revascularization in Alberta, Canada. Outcomes were survival to discharge, and a composite of heart failure hospitalization, cardiac arrest hospitalization, and all-cause mortality at 1 and 5 years. ResultsThere were 1679 patients included with an index AMI who required revascularization: 655 (39.0%) NSTEMI and 1024 (61.0%) STEMI. The population was disproportionately male (86%), particularly in STEMI patients (87.3%). Marked dyslipidemia (35%) and active smoking (42%) were common, with similar rates among groups. Percutaneous coronary intervention was used in 98.7% of STEMI and 91.5% of NSTEMI patients (P < 0.001), with the remainder who underwent surgical revascularization. The in-hospital mortality rate during index AMI was higher in STEMI compared with NSTEMI patients (1.7% vs 0%; P < 0.001). The rates of the composite outcome were similar for both groups at 1 and 5 years of follow-up in patients who survived to index hospital discharge. After adjusting for sex, age, heart failure and/or cardiac arrest at index AMI, outcomes remained similar among groups at 1 and 5 years. ConclusionsIn young patients with AMI, STEMI was a disproportionately male phenomenon and associated with higher mortality at index hospitalization. One-year and 5-year outcomes were similar among STEMI and NSTEMI patients in those discharged alive at index AMI. Smoking and dyslipidemia appear to be major risk factors in the young.

Temporal evolution of anxiety and depression in chronic heart failure and its association with clinical outcome

BackgroundAlthough anxiety and depression have been associated with adverse outcomes in chronic heart failure (HF), data on temporal evolution of these symptoms are scarce. We aimed to investigate the association between repeatedly measured depression and anxiety symptoms and clinical outcome in chronic HF patients. MethodsIn this prospective observational study, outpatients with chronic HF were included and followed-up for a maximum of 2.5 years. The hospital anxiety and depression scale (HADS) questionnaire was conducted every six months. The primary endpoint was a composite of HF hospitalization, cardiovascular death, heart transplantation and left ventricular assist device (LVAD) implantation. Cox and joint models were used to investigate the association between the HADS score and the endpoint. ResultsA total of 362 patients filled out a median (25th–75th percentile) of 3 [2–4] questionnaires each. Mean ± SD age was 63 ± 13 years, 72% were men. Anxiety scores remained relatively stable leading up to the endpoint, while depression scores increased. Higher baseline depression scores were significantly associated with the endpoint (hazard ratio [HR] 1.68 and 95% confidence interval [CI] 1.19–2.36 per log(score+1), p = 0.003), while higher baseline anxiety scores did not reach statistical significance (HR [95% CI] 1.34 [0.99–1.83], p = 0.061). When repeatedly measured, both higher anxiety (HR [95% CI] 1.57[1.07–2.30], p = 0.022) and depression (HR [95% CI] 2.04 [1.39–3.06], p < 0.001) scores were significantly associated with the endpoint. ConclusionSerial measurements of depression and anxiety symptoms identify chronic HF patients with increased risk of adverse clinical outcomes. Screening for both disorders should be considered in clinical practice.

Retrograde Conduction in Left Bundle Branch Block: Insights From Left Bundle Branch Pacing.

Biventricular pacing is a well-established therapy for patients with heart failure (HF), left bundle branch block (LBBB) and left ventricular (LV) dysfunction. Left bundle branch pacing (LBBP) has emerged as an alternative to biventricular pacing. The aim of this study was to assess the retrograde conduction properties of the left bundle branch in patients with nonischemic cardiomyopathy and LBBB during LBBP and its clinical implications. Patients undergoing successful LBBP for nonischemic cardiomyopathy with LV ejection fraction (LVEF)≤35% and LBBB were included. Continuous recording of His potential was performed using a quadripolar catheter. Unidirectional block was defined as retrograde His bundle activation during LBBP with stimulus to His potential (SH) duration less than or equal to antegrade HV interval and bidirectional block as VH dissociation or SH duration greater than HV interval. HF hospitalization, ventricular arrhythmias, and mortality were documented. A total of 165 patients were included. The mean follow-up duration was 21.8 ± 13.1months. Bidirectional block (group I) was observed in 82% (n=136), and these patients were noted to have advanced HF stage and prolonged baseline QRS duration. Unidirectional block (group II) with intact retrograde conduction was observed in 18% (n=29) and was associated with narrow paced QRS duration and higher LVEF during follow-up. Super-response (LVEF≥50%) was observed in 54.4% (n=74) in group I compared with 73.3% (n=22) in group II (P=0.03). The OR for LVEF normalization was 4.1 (95%CI: 1.26-13.97; P=0.02), with unidirectional block compared with bidirectional block in patients with LBBB and LV dysfunction. Adverse clinical outcomes as measured by a composite of HF hospitalization, ventricular arrhythmias, and mortality were significantly higher in group I compared with group II (12.5% vs 0%; P=0.04). Bidirectional block in LBBB was characterized by advanced HF symptoms, while unidirectional block was associated with better clinical outcomes after cardiac resynchronization therapy by LBBP.

Effects of different sodium–glucose cotransporter 2 inhibitors in heart failure with reduced or preserved ejection fraction: a network meta-analysis

BackgroundThis systematic review and meta-analysis aimed to explore the effects of different sodium–glucose cotransporter-2 inhibitors (SGLT2i) on prognosis and cardiac structural remodeling in patients with heart failure (HF).MethodsRelevant studies published up to 20 March 2024 were retrieved from PubMed, EMBASE, Web of Science, and Cochrane Library CNKI, China Biomedical Literature Service, VIP, and WanFang databases. We included randomized controlled trials of different SGLT2i and pooled the prognosis data of patients with HF. We compared the efficacy of different SGLT2i in patients with HF and conducted a sub-analysis based on left ventricular ejection fraction (LVEF).ResultsWe identified 77 randomized controlled trials involving 43,561 patients. The results showed that SGLT2i significantly enhanced outcomes in HF, including a composite of hospitalizations for HF and cardiovascular death, individual hospitalizations for HF, Kansas City Cardiomyopathy Questionnaire (KCCQ) scores, left atrial volume index (LAVi), and LVEF among all HF patients (P &amp;lt; 0.05) compared to a placebo. Sotagliflozin was superior to empagliflozin [RR = 0.88, CI (0.79–0.97)] and dapagliflozin [RR = 0.86, CI (0.77–0.96)] in reducing hospitalizations for HF and CV death. Dapagliflozin significantly reduced hospitalizations [RR = 0.51, CI (0.33–0.80)], CV death [RR = 0.73, CI (0.54–0.97)], and all-cause mortality [RR = 0.69, CI (0.48–0.99)] in patients with HF with reduced ejection fraction (HFrEF). SGLT2i also plays a significant role in improving cardiac remodeling and quality of life (LVMi, LVEDV, KCQQ) (P &amp;lt; 0.05). Among patients with HF with preserved ejection fraction (HFpEF), SGLT2i significantly improved cardiac function in HFpEF patients (P &amp;lt; 0.05). In addition, canagliflozin [RR = 0.09, CI (0.01–0.86)] demonstrated greater safety compared to sotagliflozin in a composite of urinary and reproductive infections of HFpEF patients.ConclusionOur systematic review showed that SGLT2i generally enhances the prognosis of patients with HF. Sotagliflozin demonstrated superiority over empagliflozin and dapagliflozin in a composite of hospitalization for HF and CV death in the overall HF patients. Canagliflozin exhibited greater safety compared to sotagliflozin in a composite of urinary and reproductive infections of HFpEF. Overall, the efficacy of SGLT2i was greater in HFrEF patients than in HFpEF patients.

Association of Renin-Angiotensin-Aldosterone System Inhibitors With Clinical Outcomes, Hemodynamics, and Myocardial Remodeling Among Patients With Advanced Heart Failure on Left Ventricular Assist Device Support.

We evaluated the potential benefits of renin-angiotensin-aldosterone system inhibitors (RAASi) in patients with left ventricular assist device support. A total of 165 consecutive patients undergoing left ventricular assist device implant and alive at 6-month on support were studied. RAASi status after 6-month visit along with clinical reasons for nonprescription/uptitration were retrospectively assessed. The primary outcome was a composite of heart failure hospitalization or cardiovascular death between 6 and 24 months after left ventricular assist device implant. Remodeling and hemodynamic outcomes were explored by studying the association of RAASi new prescription/uptitration versus unmodified therapy at 6-month visit with the change in echocardiographic parameters and hemodynamics between 6 and 18 months. After the 6-month visit, 76% of patients were on RAASi. Patients' characteristics among those receiving and not receiving RAASi were mostly similar. Of 85 (52%) patients without RAASi new prescription/uptitration at 6-month visit, 62% had no apparent clinical reason. RAASi were independently associated with the primary outcome (adjusted hazard ratio, 0.31 [95% CI, 0.16-0.69]). The baseline rates of optimal echocardiographic profile (neutral interventricular septum, mitral regurgitation less than mild, and aortic valve opening) and hemodynamic profile (cardiac index ≥2.2 L/min per m2, wedge pressure <18 mm Hg, and right atrial pressure <12 mm Hg) were similar between groups. At 18 months, patients receiving RAASi new prescription/uptitration at 6 months had higher rates of optimal hemodynamic profile (57.5% versus 37.0%; P=0.032) and trends for higher rates of optimal echocardiographic profile (39.6% versus 22.9%; P=0.055) compared with patients with 6-month unmodified therapy. Optimal 18-month hemodynamic and echocardiographic profiles were associated with the primary outcome (log-rank=0.022 and log-rank=0.035, respectively). RAASi are associated with improved outcomes and improved hemodynamics among mechanically unloaded patients.

Glucagon-like peptide-1 receptor agonists use and associations with outcomes in heart failure and type 2 diabetes: data from the Swedish Heart Failure and Swedish National Diabetes Registries.

To assess the use and associations with outcomes of glucagon-like peptide-1 receptor agonists (GLP-1 RA) in a real-world population with heart failure (HF) and type 2 diabetes mellitus (T2DM). The Swedish HF Registry was linked with the National Diabetes Registry and other national registries. Independent predictors of GLP-1 RA use were assessed by multivariable logistic regressions and associations with outcomes were assessed by Cox regressions in a 1:1 propensity score-matched cohort. Of 8188 patients enrolled in 2017-21, 9% received a GLP-1 RA. Independent predictors of GLP-1 RA use were age <75 years, worse glycaemic control, impaired renal function, obesity, and reduced ejection fraction (EF). GLP-1 RA use was not significantly associated with a composite of HF hospitalization (HHF) or cardiovascular (CV) death regardless of EF, but was associated with a lower risk of major adverse CV events (CV death, non-fatal stroke/transient ischaemic attack, or myocardial infarction), and CV and all-cause death. In patients with body mass index ≥30 kg/m2, GLP-1 RA use was also associated with a lower risk of HHF/CV death and HHF alone. In patients with HF and T2DM, GLP-1 RA use was independently associated with more severe T2DM, reduced EF, and obesity and was not associated with a higher risk of HHF/CV death but with longer survival and less major CV adverse events. An association with lower HHF/CV death and HHF was observed in obese patients. Our findings provide new insights into GLP-1 RA use and its safety in HF and T2DM.

Effect of Empagliflozin on Heart Failure Outcomes After Acute Myocardial Infarction: Insights From the EMPACT-MI Trial.

Empagliflozin reduces the risk of heart failure (HF) events in patients with type 2 diabetes at high cardiovascular risk, chronic kidney disease, or prevalent HF irrespective of ejection fraction. Whereas the EMPACT-MI trial (Effect of Empagliflozin on Hospitalization for Heart Failure and Mortality in Patients With Acute Myocardial Infarction) showed that empagliflozin does not reduce the risk of the composite of hospitalization for HF and all-cause death, the effect of empagliflozin on first and recurrent HF events after myocardial infarction is unknown. EMPACT-MI was a double-blind, randomized, placebo-controlled, event-driven trial that randomized 6522 patients hospitalized for acute myocardial infarction at risk for HF on the basis of newly developed left ventricular ejection fraction of <45% or signs or symptoms of congestion to receive empagliflozin 10 mg daily or placebo within 14 days of admission. In prespecified secondary analyses, treatment groups were analyzed for HF outcomes. Over a median follow-up of 17.9 months, the risk for first HF hospitalization and total HF hospitalizations was significantly lower in the empagliflozin compared with the placebo group (118 [3.6%] versus 153 [4.7%] patients with events; hazard ratio, 0.77 [95% CI, 0.60, 0.98]; P=0.031, for first HF hospitalization; 148 versus 207 events; rate ratio, 0.67 [95% CI, 0.51, 0.89]; P=0.006, for total HF hospitalizations). Subgroup analysis showed consistency of empagliflozin benefit across clinically relevant patient subgroups for first and total HF hospitalizations. The need for new use of diuretics, renin-angiotensin modulators, or mineralocorticoid receptor antagonists after discharge was less in patients randomized to empagliflozin versus placebo (all P<0.05). Empagliflozin reduced the risk of HF in patients with left ventricular dysfunction or congestion after acute myocardial infarction. URL: https://www.clinicaltrials.gov; Unique identifier: NCT04509674.

Cardiorenal effectiveness of empagliflozin vs. glucagon-like peptide-1 receptor agonists: final-year results from the EMPRISE study

BackgroundNo randomized clinical trials have directly compared the cardiorenal effectiveness of empagliflozin and GLP-1RA agents with demonstrated cardioprotective effects in patients with a broad spectrum of cardiovascular risk. We reported the final-year results of the EMPRISE study, a monitoring program designed to evaluate the cardiorenal effectiveness of empagliflozin across broad patient subgroups.MethodsWe identified patients ≥ 18 years old with type 2 diabetes who initiated empagliflozin or GLP-1RA from 2014 to 2019 using US Medicare and commercial claims databases. After 1:1 propensity score matching using 143 baseline characteristics, we evaluated risks of outcomes including myocardial infarction (MI) or stroke, hospitalization for heart failure (HHF), major adverse cardiovascular events (MACE – MI, stroke, or cardiovascular mortality), a composite of HHF or cardiovascular mortality, and progression to end-stage kidney disease (ESKD) (in patients with chronic kidney disease stages 3–4). We estimated hazard ratios (HR) and rate differences (RD) per 1,000 person-years, overall and within subgroups of age, sex, baseline atherosclerotic cardiovascular disease (ASCVD), and heart failure (HF).ResultsWe identified 141,541 matched pairs. Compared with GLP-1RA, empagliflozin was associated with similar risks of MI or stroke [HR: 0.99 (0.92, 1.07); RD: -0.23 (-1.25, 0.79)], and lower risks of HHF [HR: 0.50 (0.44, 0.56); RD: -2.28 (-2.98, -1.59)], MACE [HR: 0.90 (0.82, 0.99); RD: -2.54 (-4.76, -0.32)], cardiovascular mortality or HHF [HR: 0.77 (0.69, 0.86); RD: -4.11 (-5.95, -2.29)], and ESKD [0.75 (0.60, 0.94); RD: -6.77 (-11.97, -1.61)]. Absolute risk reductions were larger in older patients and in those with baseline ASCVD/HF. They did not differ by sex.ConclusionsThe cardiovascular benefits of empagliflozin vs. cardioprotective GLP-1RA agents were larger in older patients and in patients with history of ASCVD or HF, while they did not differ by sex. In patients with advanced CKD, empagliflozin was associated with risk reductions of progression to ESKD.

Early changes in estimated glomerular filtration rate post-initiation of empagliflozin in EMPEROR-Preserved.

Renal function (estimated glomerular filtration rate [eGFR]) changes early after the introduction of empagliflozin have not been described in heart failure with preserved ejection fraction (HFpEF). The aim of this study was to describe early eGFR changes, assess its determinants and its clinical impact on cardiovascular and renal outcomes in patients with HFpEF enrolled in EMPEROR-Preserved. Estimated glomerular filtration rate changes (absolute and relative) from randomization to week 4 were calculated and landmark analyses performed. Initial eGFR change was available in 5836 patients (97.5% of the population). Empagliflozin induced a mean eGFR change of -3.2 ml/min/1.73 m2 versus placebo from baseline to week 4. After week 4, in the empagliflozin group, the risk of the primary outcome (composite of heart failure hospitalization or cardiovascular death), cardiovascular, all-cause mortality and sustained ≥50% eGFR decrease or end-stage renal disease (ESRD) did not differ by eGFR change levels. In contrast, in the placebo group, patients included in the tertile with most profound eGFR decrease (i.e. ≥5.1% from baseline) had a higher risk of the primary outcome (hazard ratio [HR] 1.46, 95% confidence interval [CI] 1.17-1.82), cardiovascular mortality (HR 1.38, 95% CI 1.01-1.89) and sustained ≥50% eGFR decrease or ESRD (HR 2.20, 95% CI 1.20-4.04) versus tertile with eGFR increase. An initial relatively small eGFR decrease may be expected after empagliflozin initiation. Such small eGFR decrease was not associated with adverse cardiovascular outcomes with empagliflozin. In contrast, eGFR decrease was associated with poor cardiovascular outcomes with placebo.

Clinical Impact of the Volumetric Quantification of Ventricular Secondary Mitral Regurgitation by Three-Dimensional Echocardiography

The assessment of ventricular secondary mitral regurgitation (v-SMR) severity through effective regurgitant orifice area (EROA) and regurgitant volume (RegVol) calculations using the proximal isovelocity surface area (PISA) method and the two-dimensional echocardiography volumetric method (2DEVM) is prone to underestimation. Accordingly, we sought to investigate the accuracy of the three-dimensional echocardiography volumetric method (3DEVM) and its association with outcomes in v-SMR patients. We included 229 patients (70±13years, 74% men) with v-SMR. We compared EROA and RegVol calculated by the 3DEVM, 2DEVM, and PISA methods. The end point was a composite of heart failure hospitalization and death for any cause. After a mean follow-up of 20±11months, 98 patients (43%) reached the end point. Regurgitant volume and EROA calculated by 3DEVM were larger than those calculated by 2DEVM and PISA. Using receiver operating characteristic curve analysis, both EROA (area under the curve, 0.75; 95% CI, 0.68-0.81; P=.008) and RegVol (AUC, 0.75; 95% CI, 0.68-0.82; P=.02) measured by 3DEVM showed the highest association with the outcome at 2years compared to PISA and 2DEVM (P<.05 for all). Kaplan-Meier analysis demonstrated a significantly higher rate of events in patients with EROA ≥ 0.3cm2 (cumulative survival at 2years: 28%±7% vs 32%±10% vs 30%±11%) and RegVol ≥ 45mL (cumulative survival at 2years: 21%±7% vs 24%±13% vs 22%±10%) by 3DEVM compared to those by PISA and 2DEVM, respectively. In Cox multivariable analysis, 3DEVM EROA remained independently associated with the end point (hazard ratio, 1.02, 95% CI, 1.00-1.05; P=.02). The model including EROA by 3DEVM provided significant incremental value to predict the combined end point compared to those using 2DEVM (net reclassification index=0.51, P=.003; integrated discrimination index=0.04, P=.014) and PISA (net reclassification index=0.80, P<.001; integrated discrimination index=0.06, P<.001). Effective regurgitant orifice area and RegVol calculated by 3DEVM were independently associated with the end point, improving the risk stratification of patients with v-SMR compared to the 2DEVM and PISA methods.

Effects of empagliflozin on collagen biomarkers in patients with heart failure: Findings from the EMPEROR trials.

Extracellular matrix remodelling is one of the key pathways involved in heart failure (HF) progression. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) may have a role in attenuating myocardial fibrosis. The impact of SGLT2i on blood markers of collagen turnover in humans is not fully elucidated. This study aimed to investigate the effect of empagliflozin on serum markers of collagen turnover in patients enrolled in the EMPEROR-Preserved and EMPEROR-Reduced trials. Overall, 1084 patients (545 in empagliflozin and 539 in placebo) were included in the analysis. Procollagen type I carboxy-terminal propeptide (PICP), a fragment of N-terminal type III collagen (PRO-C3), procollagen type I amino-terminal peptide (PINP), a fragment of C-terminal type VIa3 collagen (PRO-C6), a fragment of type I collagen (C1M), and a fragment of type III collagen (C3M) were measured in serum at baseline, 12 and 52 weeks. A mixed model repeated measurements model was used to evaluate the effect of empagliflozin versus placebo on the analysed biomarkers. Higher baseline PICP, PRO-C6 and PINP levels were associated with older age, a more severe HF presentation, higher levels of natriuretic peptides and high-sensitivity troponin T, and the presence of comorbid conditions such as chronic kidney disease and atrial fibrillation. Higher PICP levels were associated with the occurrence of the study primary endpoint (a composite of HF hospitalization or cardiovascular death), and PRO-C6 and PINP were associated with the occurrence of sustained worsening of kidney function. On the other hand, PRO-C3, C1M, and C3M were not associated with worse HF severity or study outcomes. Compared to placebo, empagliflozin reduced PICP at week 12 by 5% and at week 52 by 8% (week 12: geometric mean ratio = 0.95, 95% confidence interval [CI] 0.91-0.99, p = 0.012; week 52: geometric mean ratio = 0.92, 95% CI 0.88-0.97, p = 0.003). Additionally, empagliflozin reduced PRO-C3 at week 52 by 7% (week 12: geometric mean ratio = 0.98, 95% CI 0.95-1.02, p = 0.42; week 52: geometric mean ratio = 0.93, 95% CI 0.89-0.98, p = 0.003), without impact on other collagen markers. Our observations are consistent with experimental observations that empagliflozin down-regulates profibrotic signalling. The importance of such an effect for the clinical benefits of SGLT2i in HF remains to be elucidated.

Sodium-glucose cotransporter-2 inhibitors improve clinical outcomes in patients with type 2 diabetes mellitus undergoing anthracycline-containing chemotherapy: an emulated target trial using nationwide cohort data in South Korea

Novel hypoglycemic agents, sodium-glucose cotransporter 2 inhibitors (SGLT2i), have shown protective effects against anthracycline (AC)-induced cardiotoxicity and exhibit partial anticancer effects in animal models. However, clinical evidence for this is scarce. This study aimed to evaluate whether SGLT2i improve the clinical outcomes of patients with type 2 diabetes mellitus (T2DM) undergoing AC-containing chemotherapy. A total of 81,572 patients who underwent AC chemotherapy between 2014 and 2021 were recruited from a nationwide Korean cohort. Patients were classified into three groups: patients with T2DM taking SGLT2i (n = 780) and other hypoglycemic agents excluding SGLT2i (non-SGLT2i; n = 3,455) during AC chemotherapy, and the non-DM group (n = 77,337). The clinical outcome was a composite of heart failure hospitalization, acute myocardial infarction, ischemic stroke, and death. After propensity score matching, 779 SGLT2i users were compared with 7800 non-DM patients and 2,337 non-SGLT2i users. The SGLT2i group had better composite outcomes compared with the non-DM group (adjusted hazard ratio [HR] = 0.35, 95% confidence interval [95% CI] = 0.25–0.51) and compared with the non-SGLT2i group (adjusted HR = 0.47, 95% CI = 0.32–0.69). In conclusion, SGLT2i may contribute to improving clinical outcomes in patients with T2DM undergoing AC-containing chemotherapy, through an emulated target trial using Korean nationwide cohort data.