Effects of Dapagliflozin in Heart Failure According to Duration of Type 2 Diabetes: A Patient-Level Meta-Analysis Of DAPA-HF And DELIVER
Type 2 diabetes (T2D) is a frequent comorbidity in heart failure (HF), and long-standing T2D is correlated with severe outcomes. Bonini J, presented a session held at the European Society of Cardiology (ESC) Congress on 30th August 2024, in London, UK to assess the benefit and safety of dapagliflozin, compared with placebo, as per the duration of T2D in patients with HF and established T2D.
A patient-level pooled analysis of the DAPA-HF and DELIVER trials was conducted, which analysed the impacts of dapagliflozin, compared with placebo, in patients with HF with reduced ejection fraction and HF with mildly reduced/preserved ejection fraction, respectively. T2D duration was classified as <5 years, 6-10 years, and >11 years. The primary outcome was a composite of worsening HF or cardiovascular death.
From the 4,784 patients with a history of T2D, 1,879 (39.3%) patients showed a T2D duration of <5 years, 1,074 (22.4%) 5-10 years, and 1,831 (38.3%) >11 years. Patients with longer-duration T2D were older, more often female, and White, and exhibited a higher HbA1c, body mass index, and left ventricular ejection fraction. They were more about to have ischaemic heart disease, peripheral artery disease, hypertension, and chronic kidney disease, however were less likely to have atrial fibrillation/flutter. While patients with longer-duration T2D showed longer duration of HF, they were not more about to have a prior HF hospitalization or worse NYHA functional class. Regardless of similar N-terminal pro-B-type natriuretic peptide levels, patients with longer-duration T2D showed a greater risk of the primary outcome, even after adjustment for potential confounders (<5 years, reference; 6-10 years, HR 1.25 [95% CI, 1.06-1.46]; >11 years, HR 1.33 [1.15-1.54]). The advantage of dapagliflozin on the primary outcome was constant over T2D duration group: <5 years, HR 0.85 (95% CI, 0.69-1.04); 5-10 years, HR 0.65 (0.51-0.83); >11 years, HR 0.84 (0.70-1.01) (p=0.18). Dapagliflozin showed reduction in the risk of secondary clinical outcomes and increased (enhanced) mean KCCQ scores from baseline to 8 months, despite T2D duration (Table). Adverse events and therapy discontinuation were not more common with Dapagliflozin as compared to placebo irrespective of T2D duration.
Dapagliflozin decreased the risk of worsening HF or cardiovascular death, and enhanced symptoms, in patients with HF and T2D, despite of T2D duration.
ABO Blood Groups and Platelet Reactivity in Patients with Coronary Artery Disease Undergoing Percutaneous Coronary Intervention Treated with Clopidogrel
The correlation among ABO blood groups and the risk of thrombosis and bleeding in patients with coronary artery disease has been of interest for many years, however the procedures are not fully understood. Li J, presented a session held at the European Society of Cardiology (ESC) Congress on 30th August 2024, in London, UK to analyse the association among the ABO blood groups and the platelet reactivity in patients with coronary artery disease undergoing percutaneous coronary intervention (PCI) managed with clopidogrel.
10,724 consecutive PCI patients were assessed in China from January 2013 to December 2013. Between them, 6,740 patients showed the results of thromborlastogram (TEG) and the ABO blood groups. Low on-treatment platelet reactivity (LTPR) was described as adenosine diphosphate-induced platelet maximum amplitude of TEG<31mm.
A total of 6,740 PCI patients (mean age, 58.23±10.27; male, 77.6%) treated with clopidogrel were finally enlisted for examination. There were 2560 (37.98%) patients in LTPR group. In this group, the multivariate logistic regression exhibited that the blood group A (OR: 0.885, 95%CI 0.789-0.993, p=0.038) was independent protective factor in the A/non-A model (model 1). Also, the non-A groups were divided into B, O, AB groups to set the model 2. In model 2, multivariate logistic regression exhibited that only the blood group B (OR: 1.157, 95%CI 1.015-1.320, p=0.030) was independent risk predictors for LTPR, indicating a greater risk of bleeding as compared to A group.
PCI patients managed with clopidogrel showed the correlation among ABO blood groups and platelet reactivity for the first time in this large sample real-world study. Blood group A was an independent protective factor for LTPR, indicating a lower risk of bleeding, conversely blood group B was an independent risk factor for LTPR, exhibiting a higher risk of bleeding. These findings provide an interesting perspective on blood groups and individualized antithrombotic treatment in patients with coronary artery disease, and additional explanation of the procedures is still required in the future.
Effects of Sacubitril/Valsartan on All-Cause Hospitalizations in Heart Failure: Participant-Level Pooled Analysis of PARADIGM-HF and PARAGON-HF
Sacubitril/valsartan is demonstrated to decrease the risk of cardiovascular (CV) death and heart failure (HF) hospitalizations in patients with chronic HF. But, many of these patients are older and have multiple comorbidities that increase the risk of hospitalizations other than HF, still the impacts of sacubitril/valsartan on hospitalizations of any cause have not been well defined.
Lu H, presented a session held at the European Society of Cardiology (ESC) Congress on 30th August 2024, in London, UK. PARADIGM-HF and PARAGON-HF were phase-3, global multicenter randomized clinical trials that assessed sacubitril/valsartan versus enalapril (in PARADIGM-HF) or valsartan (in PARAGON-HF) over the spectrum of left ventricular ejection fraction (LVEF; ≤40% in PARADIGM-HF and ≥45% in PARAGON-HF). An individual participant-level data from these 2 trials was pooled to analyse the effects of sacubitril/valsartan on time-to-first investigator-reported all-cause and cause-specific hospitalization by Cox proportional hazards models, categorised by geographic region and trial. Furthermore, heterogeneity was analysed in management response using LVEF.
Across 2.8 years median follow-up, between 13,194 participants in the pooled PARADIGM-HF/PARAGON-HF, sacubitril/valsartan substantially decreased the risk of all-cause hospitalizations compared with renin-angiotensin system inhibitor (HR 0.92; 95% CI 0.88-0.97; p=0.002); Figure 1 Panel A. The absolute risk reduction (ARR) was 2.1 per 100 patient-years corresponding to a number-needed-to-treat (NNT) of 48 patient-years of treatment exposure to prevent 1 all-cause hospitalization. Reductions in overall hospitalizations between patients with identifiable causes (N=5,783) appeared to be mainly due to lower rates of cardiac and pulmonary hospitalizations correlated with sacubitril/valsartan. Patients managed with sacubitril/valsartan did not have a greater rate of composite non-cardiac hospitalizations (Figure 1 Panel B). Comparably, sacubitril/valsartan showed reduction in the risk of the composite of all-cause hospitalization or all-cause mortality (HR 0.92; 95% CI 0.87-0.96; p<0.001), with an ARR of 2.5 per 100 patients-years and an NNT of 40 patient-years. In all-cause hospitalization, substantial heterogeneity was seen by LVEF as a continuous measure (pinteraction=0.027); treatment effects were most visible in patients with an LVEF below 60% (HR 0.91 95% CI 0.86-0.96; Figure 2).
In a pooled examination of >13,000 patients with chronic HF, sacubitril/valsartan exhibited reduction in hospitalization for any reason with advantages most visible in patients with an LVEF below normal.
Absence Of Coronary Artery Disease in High-Risk Sickle Cell Anemia Patients: A New Illustration Supporting the Protective Effect of Bilirubin Against Atherosclerosis?
Sickle cell anemia (SCA) is correlated with both cardiac and systemic vascular diseases, which are the prime cause of morbidity-mortality. While these patients accumulate multiple cardiovascular (CV) risk factors, along with chronic inflammation and endothelial activation, some pre-clinical studies highlighted a paradoxical protection against atherosclerosis. Stevenard M, presented a session held at the European Society of Cardiology (ESC) Congress on 30th August 2024, in London, UK to evaluate the prevalence of coronary artery disease in a high-risk SCA population.
From January 2019 to December 2023, consecutive adult patients with SCA were prospectively incorporated in the DREPACOEUR registry to particularly assess cardiac structure and function. They all had a comprehensive CV analysis at steady-state in day-hospital including clinical exam, cardiac imaging, rhythm monitoring accompanying biology examination. Only patients that underwent coronary imaging (CT coronary angiogram) were incorporated in this study.
90 patients were enrolled in the study with mean age was 44±12, 50% were male with a high prevalence of systemic hypertension (57%), obstructive sleep apnea (21%) and 10% smokers. Only one patient showed history of diabetes but no dyslipidemia (or lipid lowering therapy) was reported. Heart function was primarily preserved with a mean left ventricular ejection fraction (LVEF) of 58±5%. Expectedly, patients exhibited low hemoglobin level 8,7±1.4g/dL with high hemolysis markers. Glomerular filtration rate was 109 [62; 122] mL/min/m² with 21% having chronic kidney disease. Plasmatic LDL-C level was low (0.7±0.3g/L, with 20% <0.5g/l) while triglycerides (TG) were highly different (1.1±0.7mg/dL). Remarkably, no patient had signs of substantial coronary artery disease, with 87% indicating a calcium score of 0, 77% patients showed a CAD-RADS of 0 while no patient was greater than 2. Correlation and linear regression examination were executed to find independent parameters related with LDL-C and TG. Total bilirubin was the only variable that associated with both LDLc and TG (R= -0.37, p<0.001 and R= -0.33, p=0.001 respectively).
Ageing SCA patients exhibited no substantial coronary artery disease in spite of systemic vasculopathy and chronic inflammation. These data are in line with pre-clinical studies recommending a lipid-lowering role of bilirubin and its protective effect against atherosclerosis.
SMART-2D: A Novel Scoring System to Predict Non-Diagnostic Exercise Stress Echocardiography in Renal Transplant Candidates
Exercise stress echocardiography (ESE) is frequently used for pre-renal transplant risk stratification. Nearly 20% of ESE may be non-diagnostic, shows delays to transplant and elevated healthcare cost. A simple, definitive tool for predicting non-diagnostic ESE may streamline analysis. Abrahams T, presented a session held at the European Society of Cardiology (ESC) Congress on 30th August 2024, in London UK.
Retrospective examination was performed on 898 kidney transplant candidates who underwent exercise stress echocardiography between 2013-2020 for pre-transplant cardiovascular analysis. The group was separated into a derivation and validation set. Multivariable logistic regression recognized predictors of non-diagnostic ESE. Covariates correlated with non-diagnostic ESE (p<0.10) on univariate analysis were incorporated in the multivariable model. From this model, only variables with p<0.05 were incorporated for score development. An area under the receiver operating curve (AUROC) was used to assess model discrimination.
Non-diagnostic ESE exhibited in 17% (151/898). Predictors of non-diagnostic study designed the scoring system: 1 point for female sex, 2 points for BMI >40, 1 point for age >55, Heart Rate<55 4 points, <65 3 points and <75 2 points. LV Hypertrophy was allocated 2 points, Type 1 Diabetes 3 points and Type 2 diabetes 1 point, LV Dysfunction was allocated 2 points. This scoring system showed excellent discriminative ability (derivation AUROC 0.80, validation AUROC 0.81). A score of 8 or more showed a specificity of 97% and a positive likelihood ratio of 9.4 for non-diagnostic ESE. A score of <8 showed a negative predictive value of 86%. Patients with Non-Diagnostic ESE exhibited longer time to transplantation (695 vs 636 days), and more analyses executed (43.05% vs 17.94%, p<0.001) and less likely to take a renal transplant (OR 0.47, p<0.001).
Non diagnostic ESE leads to substantial delays to patient care in pre-transplant evaluation. A simple clinical scoring system may recognize patients about to have non-diagnostic ESE and can be used to recognize patients who may benefit from alternative risk-stratification examinations.
Exploratory Mediation Analysis of The Effect of Semaglutide on Cardiovascular Outcomes in People with Overweight or Obesity in The SELECT Randomised Trial
GLP-1 receptor agonists exhibit reduction in major adverse C events (MACE) in people with diabetes. The SELECT trial explored effect of weekly subcutaneous semaglutide 2.4 mg versus placebo in people with pre-existing CV disease and BMI ≥27kg/m², however without diabetes at randomisation. Over follow-up of 39.8 months, patients treated with semaglutide showed lower risk of MACE vs placebo (p<0.001). Several CV risk factors had improvements; however, procedures that are main cause of the MACE reduction are unclear.
Kahn S, presented a session held at the ESC Congress on 31st August 2024, in London, UK aimed explore whether the impacts on measured CV risk factors may intervene the 20% decrease in MACE in SELECT.
CV risk factors were estimated during the trial and incorporated as potential mediators in the evaluation were: body weight, waist circumference, high-sensitivity C-reactive protein (hsCRP), HbA1c, lipids, BP, eGFR and UACR. The Vansteelandt repeated regression approach was used to perform mediation analyses. First, the observed difference in MACE-free survival among semaglutide and placebo at 36 months was measured as the total effect. The direct impact of semaglutide was measured as the difference in MACE-free survival as well, showed the semaglutide arm experienced the values of the mediator observed in the placebo arm in follow-up. The % mediation was evaluated as 100 × (1 – [direct effect]/[total effect]). A reversed counterfactual approach measuring the direct impact as the difference among arms in MACE-free survival, showed the placebo arm experienced the mediator values was also performed in the semaglutide arm.
Semaglutide showed Statistically substantial (p<0.05) enhancements in all potential mediators. Table 1 shows the estimated mediation of each potential mediator if analysed separately. Point estimates for the % mediation was highest for waist circumference (64.0%), hsCRP (42.1%), HbA1c (29.0%) and body weight (19.5%), however with wide 95% CIs. For waist circumference, the estimated mediation was significantly lower by the reversed counterfactual approach, recommending potential hidden confounding or therapy–mediator interaction (Figure 1). The estimated joint mediation was 31.4% (−30.1%, 143.6%) in a multivariable analysis.
The findings recommend that neither change in body weight nor other estimated CV risk factors fully investigate the impact of semaglutide on MACE in SELECT. Significant unestimated pleiotropic impacts of semaglutide on MACE not arbitrated via these risk factors remain possible.
Cardiovascular Prevention with GLP1 Agonists in High or Very-High Cardiovascular Risk Irrespective of Diabetes
Patients with established CV disease have an elevated risk of stroke and myocardial infarction, even in the absence of atrial fibrillation. Various trials have evaluated the impact of glucagon-like peptide-1 receptor (GLP1) agonists in patients with high CV risk and recently this impact has been calculated even in the absence of diabetes. del-Cuerpo-Salinas N, presented a session held at the ESC Congress on 31st August 2024, in London, UK.
A meta-analysis of randomized clinical trials (RCT) was executed comparing GLP1 agonists with placebo. The primary objective of the study was to assess the composite endpoint of CV death, non-fatal myocardial infarction and non-fatal stroke (MACE). As secondary objectives were CV death, non-fatal myocardial infarction and non-fatal stroke have been studied individually. The inverse variance method and the fixed effects model were used to perform the meta-analysis, when there was no heterogeneity and the random effects model was used when heterogeneity is substantial. In the case of substantial heterogeneity in the primary objective, a classified evalaution with exposure time have been executed to investigate this outcome.
A sum of 9 randomized controlled trials were incorporated in which a GLP1 agonist such as albiglutide, dulaglutide, exenatide, liraglutide, lixinatide or semaglutide was compared with placebo. 77684 patients were enrolled, while 39497 were managed with a GLP1 agonist. The mean age was of 63.7 years (SD ± 1.97 years), 60080 (77.3%) having diabetes and 60552 (77.9%) from CV disease.
The GLP1 agonists exhibited a decrease of 13% of the MACE (RR: 0.87, 95% CI 0.81-0.92; p<0.001) as showed in figure 1. Heterogeneity could be described by exposure time and concentration in the blood, contemplating that it disappears within each group when applying this condition. GLP1 agonist therapy also showed reduction in CV death by 12% (RR: 0.88, 95% CI 0.82-0.94; p<0.001), non-fatal strokes by 14% (RR: 0.86, 95%CI 0.79-0.95; p<0.001) and non-fatal myocardial infarction by 13% (RR: 0.87, 95% CI 0.78-0.97; p<0.001).
GLP1 agonist therapy exhibited reduction in the occurrence of the MACE by 13% and CV death by 12%, besides it reduced the occurrence of nonfatal stroke by 14% and of nonfatal myocardial infarction by 13% in different RCTs including patients with high or very-high CV risk with or without diabetes.
Real World Evidence of Sacubitril/Valsartan in Octogenarian Patients with Heart Failure. Results From The PARACHUTE-HF Study
The advantageous effects of Angiotensin Receptor Neprilysin Inhibitors (ARNI) on heart failure (HF) patients, especially those with reduced left ventricular ejection fraction (LVEF), have been emphasized in various randomized controlled trials. Before 2020, ARNI has been available for HF treatment in Japan, a country known for its aging population. But, the addition of octogenarians in previous trials has been restricted, leaving a gap in evidence concerning ARNI’s efficacy in the elderly.
Okuda N, presented a session held at the European Society of Cardiology (ESC) Congress on 31th August 2024, in London, UK aims to investigate the real-world effectiveness and safety of ARNI therapy between octogenarian HF patients in Japan, reflecting its status as a dominant aging society.
A multicenter registry was conducted the PARACHUTE (Prospective Area Registry of ARNI for Congestive Heart failUre in Tokyo East) trial. Patients with newly prescribed ARNI for chronic HF regardless of LVEF between 2020 and 2021 were enrolled in the study. Patient backgrounds, changes in NT-proBNP levels at 6 months, and the rate of ARNI discontinuation were compared among groups aged below and above 80 years.
105 patients were enlisted in the study, with an average age of 75 years. 46 patients (44%) were above 80 years old, and the majority (72%) were male. In the younger group, higher no. of patients showed preserved LVEF as compared to the octogenarian group (50% vs 32%) (p=0.01). All patients showed substantial reduction in median NT-proBNP levels from 2,540 pg/mL at baseline to 998 pg/mL at 6 months. While the two age groups showed similar reduction in NT-proBNP, with no substantial interaction (p=0.46). Discontinuation rates because of any cause were not substantially variable among younger and older patients (7% vs. 13%, p=0.28).
ARNI therapy exhibited substantial reductions in NT-proBNP levels in HF patients, both under and over 80 years of age, with similar discontinuation rates. These results emphasize the efficacy and safety of ARNI in the treatment of chronic HF in the elderly, presenting valuable real-world indication from Japan’s unique demographic context.
Effect Of Sodium-Glucose Cotransporter-2 Inhibitor (SGLT2-I) In Patients With LVAD: A Systematic Review and Meta-Analysis
Sodium-glucose cotransporter-2 inhibitors (SGLT2-i) have been shown to reduce risks of clinical events in patients with heart failure (HF). Nevertheless, data on the use of SGLT2-i in patients with left ventricular assist devices (LVAD) are scarce. Hasabo EA presented at a session, a study that was conducted to assess the efficacy and safety of SGLT2-i in patients with LVAD, held at the European Society of Cardiology (ESC) Congress from 30th August to 2nd September 2024, in London.
A systematic search was conducted across PubMed, Scopus, Web of Science, Embase, and Cochrane databases up to December 2023, focusing on studies and abstracts related to the use of SGLT2 inhibitors in patients with LVAD. Data on efficacy and safety were extracted, and a meta-analysis was performed using RevMan 5.4.1. The analysis included 3 studies and 8 abstracts, totaling 209 patients treated with Empagliflozin, Dapagliflozin, or Canagliflozin. SGLT2 inhibitors significantly reduced hemoglobin A1c (Mean = -0.44) and diuretic doses (Mean = -2.54) but did not significantly improve GFR, BNP, or MPAP. The pooled incidence of driveline infection was 9.33%.
SGLT2-i effectively improves HbA1c and diuretic dose in patients using LVAD. Further randomized studies with a large number of participants may be warranted.
Metoprolol Therapy in Patients with Eisenmenger Syndrome (MINES) Study. A Single-Centre, Double-Blinded, Randomized, Placebo-Controlled Trial
Eisenmenger syndrome is common in developing countries due to limited neonatal screening and surgical options. This double-blind, placebo-controlled trial assessed the effects of metoprolol succinate (25 mg daily for 2 weeks, then 25 mg twice daily for 14 weeks) in 60 patients with Eisenmenger syndrome. The primary outcome was the change in the 6-minute walk test (6MWT) distance. Secondary outcomes included clinical events, resting saturation, TAPSE, and NT-proBNP levels.
To study the safety and efficacy of metoprolol succinate therapy in patients with Eisenmenger syndrome Pius S, presented a session held at the European Society of Cardiology (ESC) Congress from 30th August to 2nd September 2024, in London.
Study results suggested that there was no significant difference in 6MWT distance between metoprolol and placebo groups. The clinical composite outcome occurred more frequently in the metoprolol group (17%) compared to the placebo group (3%) but did not reach statistical significance. NT-proBNP levels increased by 37% in the metoprolol group versus a 13% decrease in the placebo group. No significant differences were found in TAPSE or resting saturation between the groups.
Metoprolol succinate therapy did not improve the 6-minute walk distance at 16 weeks among patients with Eisenmenger syndrome compared to placebo. Metoprolol succinate therapy was associated with increased clinical composite outcomes, primarily driven by the worsening of heart failure.
