NT-proBNP Levels Research Articles

Rare transthyretin gene variants (p.Ala45Thr, p.Val91Ala, p.Phe53Cys, p.Ala101Val, p.Glu109Lys and p.Phe53Leu): diagnostic pitfalls and clinical characteristics of Polish patients with transthyretin cardiac amyloidosis.

The knowledge about clinical features of Polish patients with hereditary type of transthyretin cardiac amyloidosis (ATTR-CA) is scant. We present rare transthyretin (TTR) gene variants and diagnostic difficulties among patients with hereditary ATTR-CA. In 2018-2024, 252 consecutive patients with suspected cardiac amyloidosis were evaluated, including blood tests, standard 12-lead electrocardiography, transthoracic echocardiography and [99mTc]Tc-DPD scintigraphy. TTR gene sequencing was performed, if mandatory. Hereditary ATTR-CA was confirmed in 14 patients (including one female). Most of them had pathogenic or likely pathogenic TTR gene variants, which are very uncommon in the hereditary transthyretin amyloidosis population: p.Ala45Thr, p.Val91Ala, p.Phe53Cys, p.Ala101Val, p.Glu109Lys and p.Phe53Leu. Of note, patients with p.Ala101Val and p.Phe53Cys variants had inconclusive [99mTc]Tc-DPD scintigraphy results, which may be due to the low sensitivity of [99mTc]Tc-DPD bone scintigraphy for these variants. Cardiac biomarkers did not reflect the intensity of cardiac uptake on [99mTc]Tc-DPD bone scintigraphy - two patients with intense cardiac uptake of tracer had normal or borderline hs-cTnT and NT-proBNP levels. During follow-up, four patients died, two patients underwent combined heart and liver transplantation. This study enriches our knowledge regarding genotype-phenotype correlations of specific TTR variants, broadens the spectrum of identified TTR variants among Polish population, and shows limited value of [99mTc]Tc-DPD scintigraphy in some patients with hereditary ATTR-CA. In cases with strong suspicion of ATTR-CA and inconclusive [99mTc]Tc-DPD scintigraphy results, genetic testing should be considered.

Outcomes and effects of sacubitril/valsartan according to NT-proBNP level in patients with heart failure: a patient-level pooled analysis of the PARADIGM-HF and PARAGON-HF trials

Abstract Background NT-proBNP levels are associated with disease severity and outcomes in patients with HF across the spectrum of LVEF. Recently, it has been suggested that the effectiveness of certain treatments may vary by NT-proBNP level with greater benefit from omecamtiv mecarbil, and smaller benefit from vericiguat, in patients with higher NT-proBNP levels. We examined the benefit of sacubitril/valsartan on outcomes across the range of NT-proBNP levels in patients with HFrEF/HFmrEF/HFpEF. Purpose To evaluate clinical outcomes, and the efficacy of sacubitril/valsartan, according to NT-proBNP levels, in patients with HFrEF/HFmrEF/HFpEF, using the pooled dataset of participants in the PARADIGM-HF and PARAGON-HF trials. Methods The PARADIGM-HF (n=8399) and PARAGON-HF (n=4822) trials enrolled patients with HF, functional limitation, and elevated NT-proBNP levels. Patients with LVEF ≤40% were randomized to sacubitril/valsartan 200 mg twice daily or enalapril 10mg twice daily in PARADIGM-HF, and those with LVEF ≥45% to sacubitril/valsartan 200 mg twice daily or valsartan 160mg twice daily in PARAGON-HF. Patients were categorized by quintiles of NT-proBNP level and using NT-proBNP as a continuous variable, analysed using restricted cubic splines. The primary outcome in the present study was the composite of cardiovascular death or HF hospitalization. Results Among the 13195 patients in the pooled PARADIGM-HF and PARAGON-HF dataset, 13142 (99.6%) patients with baseline NT-proBNP were analysed. Patients with higher NT-proBNP levels were more often male, had lower body mass index and LVEF, worse New York Heart Association functional class, worse kidney function, and more atrial fibrillation, while age was similar across NT-proBNP levels. The rate of the primary outcome (per 100 person-years) increased with NT-proBNP level: quintile 1, 5.9 (95%CI 5.3-6.5); quintile 2, 7.5 (95%CI 6.9-8.2); quintile 3, 9.0 (95%CI 8.2-9.7); quintile 4, 12.0 (95%CI 11.1-12.9); and quintile 5, 20.8 (95%CI 19.6-22.2) (Figure 1). Similar trends were observed for other outcomes. The benefit of sacubitril/valsartan was consistent across NT-proBNP levels: the hazard ratio for the primary outcome in NT-proBNP quintile 1 was 0.79 (95%CI 0.65-0.96); quintile 2, 0.87 (95%CI 0.72-1.04); quintile 3, 0.79 (95%CI 0.66-0.93); quintile 4, 0.85 (95%CI 0.73-0.99); and quintile 5, 0.86 (95%CI 0.76-0.97), P-interaction=0.86. The consistent benefit of sacubitril/valsartan was also seen when NT-proBNP was analysed as a continuous variable (Figure 2). The absolute benefit was greatest in quintile 5 of NT-proBNP; the number needed to treat for quintile 5 was 16 versus 37 for the quintile 1 for the primary endpoint. Conclusions Patients with higher NT-proBNP had worse outcomes, but the benefits of sacubitril valsartan were consistent across the range of NT-proBNP levels of participants in PARADIGM-HF and PARAGON-HF.Kaplan-Meier curvesEffect of sac/val across NT-proBNP range

The association of NT-proBNP levels in atrial fibrillation patients and 3-year risk of heart hospitalization and death

Abstract Background NT-proBNP-levels are often elevated in patients with atrial fibrillation (AF), but their clinical use and interpretation for predicting subsequent cardiovascular events has not been explored in an all-comers setting. Aim To determine whether NT-proBNP levels are associated with the risk of subsequent heart failure (CHF) and/or death in patients with AF and its relation to prior CHF diagnosis Method All patients with new-onset AF (defined by ICD-code I48) who had an NT-proBNP-level within +/- 14 days of the date of the AF date measured in a regional laboratory repository between 2000-2021 were included in the analysis cohort. Patients were categorized into NT-proBNP level (pg/mL) <1000, 1000-1999, ≥2000. If several NT-proBNP-levels were measured, the maximal value was used. The association between NT-proBNP level and the outcome CHF hospitalization and/or death within 3 years of diagnosis was assessed in Cox regression analyses adjusted for baseline characteristic and medications. Since there was an interaction (p<0.001) between Nt-proBNP-level and prior/new-onset CHF at time of AF diagnosis and no known CHF, two separate analyses were performed in patients with or new-onset CHF and those without prior CHF. Results There were 10559 patients with AF and no CHF, and 11 257 with AF and CHF. There were 14% of patients with new-onset CHF at time of new-onset AF diagnosis. These were grouped together with patients with known CHF. Patients with no prior CHF were younger (76 years (95% CI 68-83) vs 80 (72-87), p<0.001), and healthier with less often diabetes (18.4% vs 24.5%, p<0.001), prior myocardial infarction (12.0% vs 24.3%), a lower CHA2DS2-VASc score (3.0 vs 5.0, p<0.001) and a lower median NT-proBNP level (1650 pg/mL (95% CI 702-3549) vs 4240 pg/mL (2160-8860), p<0.001). Among patients with AF and no prior CHF, the incidence rate in the lowest NT-proBNP level was low, but increased with higher levels (Table). Adjusting for covariates and medications, the risk of both CHF hospitalization and CHF/death compared to the reference category NTproBNP< 1000 pg/mL was nearly 2 and 3 times higher among those who with initial NT-proBNP level 1000-1999 and ≥ 2000. Among patients with AF and known CHF, the incidence rate of CHF hospitalization or CHF hospitalization/death at the same NT-proBNP-strata was several times higher compared to patients without known CHF. Adjusting for covariates, the risk increased for CHF hospitalization or CHF/hospitalization similarly for each strata as for patients without known CHF. AF patients without known HF but with the highest elevation of NTproBNP-level had a risk of subsequent hospitalization of heart failure which was higher than those with known heart failure and lowest NTproBNP-level. Conclusion A higher NTproBNP-level in patients with AF identifies patients at higher risk of CHF hospitalization and/or death in both patients with no and prior CHF.Table

Metoprolol therapy in patients with Eisenmenger syndrome (MINES) study. A single-centre, double-blinded, randomised, placebo-controlled trial

Abstract Background Prevalence of Eisenmenger syndrome is still common in developing countries where early neonatal screening and referral for surgery is seldom possible. Limited number of drugs are available for treatment of this condition. Beta-blockers may improve functional status in these patients. Observational study has shown beta blockers to be safe and effective in improving effort intolerance in patients with Eisenmenger syndrome. Purpose To study the safety and efficacy of metoprolol succinate therapy in patients with Eisenmenger syndrome. Methods In this double-blind, placebo-controlled study, we randomly assigned 60 patients with Eisenmenger syndrome to receive placebo or to receive 25 mg of metoprolol succinate once daily for 2 weeks followed by 25 mg twice daily for 14 weeks (total of 16 weeks). The primary outcome was mean difference in 6-minute walk test (6MWT) distance. Secondary outcomes were clinical composite outcome (all-cause death, heart failure hospitalization, worsening of heart failure, change in WHO functional class, and new onset syncope), change in resting saturation, Tricuspid Annular Plane Systolic Excursion (TAPSE) and NT Pro BNP level at 16 weeks. Results At 16 weeks, the mean difference in 6MWT distance between treatment group and placebo group as per protocol analysis was 6 meters (95% confidence interval, - 7.43 to 19.49; P 0.37), and the mean difference in 6MWT distance as per intention to treat analysis was -1.1 meters (95% confidence interval, - 16.97 to 14.77; P 0.89). Clinical composite outcome occurred more in the treatment group 5(17%) as compared to the placebo group 1(3%) (P 0.197) though it did not reach statistical significance. This was primarily driven by worsening of heart failure in the treatment group. Compared to baseline metoprolol group had 37% increase in NT pro BNP level while placebo group had 13% (-313.69, 88.80) reduction in NT Pro BNP level. There was no difference in TAPSE 0.05 (95% confidence interval -0.62 to 0.72; P 0.88) or resting saturation -0.06 (95% confidence interval -0.88 to 0.75; P 0.87) between the two groups at 16 weeks Conclusion Metoprolol succinate therapy did not improve 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 worsening of heart failure.Graphic Abstract of MINES study

Natriuretic peptides, kidney function and clinical outcomes in heart failure with mildly reduced or preserved ejection fraction: pooled data from the I-PRESERVE, TOPCAT, PARAGON and DELIVER trials

Abstract Background The prognostic utility of N-terminal pro-B-type (NT-proBNP) in patients with heart failure and chronic kidney disease (CKD) is incompletely understood since elevations in NT-proBNP could be related either to decreased clearance by the kidney or to increased severity of structural heart disease. Purpose We sought to assess the association of NT-proBNP with cardiovascular and mortality outcomes in patients with heart failure and mildly reduced or preserved ejection fraction, stratified by baseline kidney function. Methods We conducted a pooled analysis of individual participants with NT-proBNP and estimated glomerular filtration rate (eGFR) measured at baseline in the I-PRESERVE, TOPCAT (Americas region), PARAGON and DELIVER trials. We evaluated the relationship between NT-proBNP and kidney function using piecewise linear regression. Using multivariable Cox and Poisson regression models, we assessed the association of NT-proBNP with clinical outcomes across different levels of eGFR (≥60, 45-<60 and <45 mL/min/1.73m2). The primary outcome was hospitalisation for heart failure or cardiovascular death. Results Among 14,831 participants (mean age 72.1 years, 50.3% female, mean eGFR 63.3 mL/min/1.73m2 and median NT-proBNP 840 pg/mL) followed for a median 33.5 months, there were 3,092 primary outcomes, 2,184 heart failure hospitalisations, 1,465 cardiovascular and 1,049 non-cardiovascular deaths. Participants in lower eGFR categories were more likely to be older, female, and have atrial fibrillation and diabetes (all p<0.001). NT-proBNP levels increased by 9%, 8%, and 23% per 10 mL/min/1.73m2 lower eGFR in patients with baseline eGFR ≥60, 45-60, and <45 mL/min/1.73m2, respectively (P for non-linearity <0.001). For any given NT-proBNP concentration, participants with eGFR <45 mL/min/1.73m2 were at highest risk (Figure 1). Each doubling in NT-proBNP was associated with a 37% relative increase in the primary outcome (HR 1.37, 95% CI 1.34-1.41), consistent across different eGFR categories (P-interaction=0.42). Association between NT-proBNP and other clinical outcomes were also consistent across different levels of kidney function (all P-interaction>0.3; Figure 1). Equivalent risk for the primary outcome was apparent at NT-proBNP levels approximately 2.5- to 3.5-fold lower in patients eGFR <45 mL/min/1.73m2, compared to those with eGFR ≥60 mL/min/1.73m2. (Figure 2). Conclusion NTproBNP is a potent predictor of risk in patients with heart failure with mildly reduced or preserved ejection fraction across the spectrum of kidney function. However, in patients with reduced kidney function, lower NT-proBNP levels confer absolute risk of cardiovascular outcomes similar to substantially higher NT-proBNP levels in patients with normal kidney function. Accordingly, interpretation of NTproBNP levels should vary according to kidney function, particularly in those with eGFR <45 mL/min/1.73m2.

Association of third-trimester N-terminal pro-brain natriuretic peptide levels and pre-eclampsia development

Abstract Background Pre-eclampsia shares numerous risk factors with cardiovascular diseases and is associated with postpartum cardiovascular complications. Natriuretic peptides, outside pregnancy valid biomarkers for detecting subclinical cardiac dysfunction, are typically elevated at the time of pre-eclampsia diagnosis. However, their role before disease manifestation is still puzzling. Aims To assess whether third-trimester natriuretic peptide levels are associated with a diagnosis of pre-eclampsia in pregnant individuals. Methods This study measured NT-proBNP levels in third-trimester samples of 1454 pregnant individuals prior to disease manifestation. Pre-eclampsia was diagnosed using the American College of Obstetrics and Gynecology (ACOG) criteria. Linear regression analyses were performed, and multivariable adjustments were done for age, body mass index (BMI), preexisting hypertension, diabetes, and chronic kidney disease. Odds ratios were calculated per doubling of NT-proBNP levels. Results Of the 1454 individuals, 118 (7.6 %) developed pre-eclampsia. The median week of gestation for blood sampling was 29.0 (IQR 28.4 – 29.4) in both groups (p = 0.68). Individuals with pre-eclampsia manifestation had higher BMI, were more often nulliparous, and had lower placental growth factor levels (all p < 0.01). Higher NT-proBNP levels were associated with a lower risk of pre-eclampsia, which persisted after controlling for confounders (adjusted odds ratio (OR), 0.84; 95 % CI, 0.70 - 1.00). This inverse relationship was particularly pronounced in cases of late-onset pre-eclampsia, defined as onset after 34 + 0 weeks of gestation. Specifically, for preterm pre-eclampsia between weeks 34 + 0 and 36 + 9, the adjusted OR was 0.78 (95 % CI, 0.56-1.09), and for term pre-eclampsia at or after week 37 + 0, the adjusted OR was 0.77 (95 % CI, 0.61 - 0.95). Conversely, a positive association was observed between NT-proBNP levels and the occurrence of early-onset pre-eclampsia < 34 + 0 weeks, with an adjusted OR of 1.69 (95 % CI, 1.00 - 2.91). Causal mediation analyses indicated that the association between higher BMI and pre-eclampsia mediated only a minor fraction (11.5 % [95 % CI, 4.3 % - 36.0 %, p < 0.01]) of the observed association. Conclusion These findings reveal the complex interplay between third-trimester NT-proBNP levels and the risk of pre-eclampsia. They unravel an inverse association for late-onset disease but a contrasting positive correlation for early-onset cases in temporal proximity to NT-proBNP assessment. The latter may reflect acute physiological responses to pre-eclampsia nearing diagnosis. However, the inverse relationship observed for later manifestations underscores the importance of further research to dissect the underlying pathophysiological mechanisms, which suggest cardiovascular maladaption to pregnancy prior to pre-eclampsia manifestation.

Incidence of acute cardiovascular hospitalizations and association with hemodynamic biomarkers in cancer patients treated with Immune Checkpoint Inhibitor therapy

Abstract Background/Introduction Immune checkpoint inhibitors (ICI) have significantly improved outcomes for several malignancies. Despite these benefits, patients with cancer face an increased risk for the development of cardiovascular disease due to mutual risk factors, similar biological mechanisms, as well as cardiotoxic side effects of therapy. Therefore, there is a pressing need for effective risk stratification strategies. Purpose This study aimed to explore the association between NT-proBNP levels and the risk of acute cardiovascular hospitalizations and death in patients who receive ICI. Methods We used electronic health records of patients treated with ICI who had available baseline NT-proBNP levels at our hospital, a tertiary academic center, between January 2017 and July 2022. The primary outcome of interest was the composite of acute cardiovascular hospitalization or death. The associations between NT-proBNP and outcomes were analyzed using cox regression models adjusted for age, sex, serum creatinine, diabetes, HF, CAD, hypertension, AF, LDL-C, and CRP. Results In total, 550 patients (35% female, median age 65 yrs) were included in the study. The median NT-proBNP levels were 272 pg/mL (IQR 102-742 pg/mL) and 388 (71%) patients had NT-proBNP levels ≥125 pg/mL. During a median FU of 67 weeks, 190 patients (35%) died, and 103 CV hospitalizations occurred in 76 patients (14%). Compared with patients with NT-proBNP concentrations <125, those with NT-proBNP concentrations ≥125 pg/ml had significantly higher event rates of the combined endpoint (12-Month KM event rates: 38% vs 21%, P<0.001). After multivariable adjustment, NT-proBNP remained independently associated with an increased risk of cardiovascular hospitalization and death (Adjusted HR for 1-SD increase in log-transformed biomarker 1.64, 95% CI 1.24 to 2.14; Figure). Conclusion These data highlight NT-proBNP levels as a valuable marker for identifying patients at increased risk of cardiovascular complications during ICI therapy.

Estimated plasma volume in heart failure with reduced ejection fraction: ACE inhibitors versus angiotensin receptor/neprilysin inhibitor in follow up

Abstract Background Estimated plasma volume status (ePVs) has been considered a biological surrogate for congestion and has been shown to be associated with post-discharge outcomes in patients with heart failure with reduced ejection fraction (HFrEF). The plasma volume status can be easily estimated by the index of the PVs according to the haemoglobin and haematocrit levels. Purpose The aim of the study was to examine the change in ePVs and N-terminal pro B-type natriuretic peptide (NT-proBNP) levels during the 12-month follow up of HFrEF patients treated with ACE inhibitors (ACEi) and angiotensin receptor/neprilysin inhibitor (ARNI). Methods We included all patients treated or diagnosed with HFrEF in our hospital from May 2021 to February 2022 and prescribed with either ACEi or ARNI among complete guideline-directed medical therapy (GDMT). We used Strauss-derived Duarte formula [ePVs= (100-Hct%) ÷ Hb] to estimate PVs during the initiation of GDMT and after 12-month follow up. Results This registry-based study included 619 patients with HFrEF, out of which 278 were prescribed with ACEi (ACEi group) and 273 with ARNI (ARNI group). There were no differences between the groups regarding age (ACEi 68 vs. ARNI 67 years, p=0.09), however, ACEi group had significantly more women (30% vs. 26% of patients, p=0.02). Patients in ACEi group were more likely to have ischemic cardiomyopathy (61 vs. 49%, p<0.01), higher estimated glomerular filtration rate (72 vs. 64 L/min/1.73m², p=0.01), while patients in ARNI group were more likely to be NYHA III class (40 vs. 48%, p=0.04). Initial ePVs (4.23 for ACEi vs. 4.20 for ARNI, p=0.46), NT-proBNP levels (3357.5 for ACEi vs. 2786 for ARNI, p=0.08), and left ventricular ejection fraction (median 35% for ACEi vs. 35% for ARNI, p=0.49) did not significantly differ between the groups. After the 12-month follow up, the change in ePVs was similar between the groups (-0.22 for ACEi vs. -0.19 for ARNI, p=0.93). Reduction of NT-proBNP levels was more prominent in ACEi group (1750.5 vs. 858.5 pg/mL, p=0.01). Mortality rate did not differ between the groups during 12-month follow up (9.71% in ACEi vs. 8.42% in ARNI, p=0.60). Conclusion In HFrEF patients both ACEi and ARNI reduced ePV and NTproBNP levels during 12-month follow up. ACEi were more potent in reducing NT-proBNP levels. Despite the more prominent reduction in NT-proBNP levels, no significant difference was observed in mortality rate during follow up between the groups.

Anemia and sideropenia in patients with decompensated heart failure

Abstract Introduction Anemia is highly prevalent in patients with heart failure (HF). In the latest ESC guidelines, intravenous. iron supplementation is recognized as substantial for improving quality of life, exercise capacity and reducing the risk of future hospitalizations in patients diagnosed with HF of reduced ejection fraction (HFrEF). We hypothesized that patients diagnosed with HF of preserved EF (HFpEF) and midly reduced EF (HFmrEF), who also exhibit iron deficiency, may benefit from intravenous iron supplementation. Method We evaluated the prevalence and parameters of anemia from medical histories of hospitalized patients with HFrEF and HFmrEF/HFpEF, from March 2023 to January 2024, and compared them to NTproBNP levels. Results We included 134 hospitalized patients with HF, mean age 71 ± 10 (41% women). Of total 134, 77 patients exhibited acute worsening of chronic HFrEF or were newly diagnosed HFrEF (group A), whereas 57/134 patients had decompensated HFmrEF/HFpEF (11 and 46, respectively - group B) whose iron status was analyzed on admission. General prevalence of anemia in all HF patients was 50.8% (cut off value - hemoglobin concentration less than 12 g/dL in women, and less than 13 g/dL in men), 54.4% of HFpEF/HFmrEF group and 48.1% of HFrEF group had anemia, 46.6% patients with anemia had EF>40%, without any statistical difference among groups (hemoglobin concentration group A/group B – 12.33±2.54/11.89­±2.63 g/dL, CV 0.2). Reduced transferrin saturation, which is defined as less than 20.0%, had 44.0% of all HF patients, and that was more common in HFrEF patients (62.0%), but statistically insignificant (group A/group B - 0.1843±0.10/0.1877±0.11, CV 0.6). Among group A and group B - 63.6% and 62.5% had transferrin saturation less than 0.2, respectively. There was no difference in the prevalence of serum ferritin <100 μg/L in group A and B (41.6% and 47.4% respectively; group A/group B – 177.26±176.7/137.01±126.6, CV 0.9). Spearman’s rank test implied no correlation between NTproBNP levels and serum ferritin or transferrin saturation. Serum iron had a mild negative (coefficient -2.8) correlation with NTproBNP levels (p<0.01). Hemoglobin concentration was associated with strong negative correlation with NTproBNP levels but with less statistical significance (coefficient -0.9 p<0.05). Conclusion Results of our study suggest that anemia and sideropenia are common in our HF population, with no difference between the spectrum of HF subgroups based on EF. There seems to be a correlation between anemia and serum iron and level of NTproBNP which may imply that anemia and low iron worsen the degree of HF decompensation.

Exploring heart failure prevalence and overlooked dimensions: a comprehensive NT Pro-BNP study in high-risk primary care patients

Abstract Background Heart failure (HF) is a prevalent syndrome linked to significant morbidity and mortality, especially in those with comorbid conditions like diabetes, hypertension, and atherosclerotic cardiovascular disease. Early detection and intervention are crucial. Natriuretic peptides, particularly NT-proBNP, are promising biomarkers for identifying at-risk individuals, but their use in primary care settings is not fully understood. Methods This prospective cohort study enrolled 874 participants aged 40 and above with documented risk factors for HF, such as diabetes mellitus, hypertension, metabolic syndrome, obesity, atherosclerotic cardiovascular disease, genetic variants for cardiomyopathy, or exposure to cardiotoxic agents. NT-proBNP levels were measured in blood samples collected at primary care clinics, and participants underwent comprehensive cardiac evaluations at a referral hospital. Clinical characteristics, laboratory findings, electrocardiography, and echocardiography results were recorded. Results The study included 874 patients with at least one risk factor for HF, with a mean age of 62.5 ± 9.1 years and 51.9% female. According to the 2022 AHA/ACC/HFSA HF Guideline, 69.1% were Stage A HF, 21.9% Stage B HF, and 9% Stage C HF. Clinical characteristics, laboratory and echocardiographic findings are shown in Picture 1. The majority had hypertension (71.1%), while other prevalent comorbidities included diabetes mellitus (43.4%), dyslipidemia (35.2%), obesity (27.1%), and atherosclerotic cardiovascular disease (26.2%). Laboratory findings showed a significant decrease in HbA1C, eGFR, LDL, triglycerides, and hemoglobin from Stage A to C HF. Median NT-proBNP levels rose from Stage A to C HF (46.4 pg/mL in Stage A, 219 pg/mL in Stage B, and 268.5 pg/mL in stage C), with 84.8% of Stage B HF patients exhibiting elevated levels. NT-proBNP levels were correlated positively with left atrial volume index, left ventricular mass index, age, E/e’, and estimated systolic pulmonary artery pressure levels. Conversely, NT-proBNP levels showed a negative correlation with estimated glomerular filtration rate and left ventricular ejection fraction. Among Stage C patients, 92.4% had HFpEF. The Picture 2 depicted the study's design and outcomes, providing a comprehensive visual representation. Conclusion NT-proBNP screening in primary care settings identified a substantial proportion of individuals with undiagnosed HF, particularly those in Stage B and Stage C. The high prevalence of HFpEF underscores the need for comprehensive evaluation and management strategies targeting this population. Early detection facilitated by NT-proBNP screening may lead to timely interventions and improved outcomes in individuals at risk for HF.

Efficacy and safety of dapagliflozin in non-diabetic patients with primary anterior ST-elevation myocardial infarction initiated in early hospital period

Abstract Background The effectiveness of SGLT2 inhibitors has been proven in all types of chronic heart failure (HFpEF, HFmrEF, and HFrEF), regardless of the presence of diabetes mellitus. There are still no clear recommendations regarding the timing of SGLT2 inhibitor administration after myocardial infarction (MI) and its influence on prognosis. It can be assumed that it is appropriate to consider the possibility that, if started quickly after the presentation of acute MI, SGLT inhibition might enhance outcomes in patients. Objective This study aims to investigate the efficacy and safety of the SGLT2 inhibitor Dapagliflozin in primary anterior ST-segment elevation myocardial infarction (STEMI) initiated in early hospital period, irrespective of heart failure manifestation. Methods The study includes 124 non-diabetic patients with primary anterior STEMI who underwent primary PCI and had left ventricular ejection fraction (LV EF) ≤45% and NT-proBNP > 900 pg/ml at symptom onset within 24 hours, regardless of heart failure symptom manifestation. Patients with cardiogenic shock were excluded. 62 patients received standard medical treatment including beta-blockers, ACE inhibitors (Control group), while the other 62 patients were administered the SGLT2 inhibitor Dapagliflozin 10 mg once a day during the first 48 hours of inpatient treatment, in addition to standard therapy (Dapa group). All patients were followed up for one year. Echocardiography was performed during the first 24 hours. Echocardiography and NT-proBNP were repeated at the end of the year. The primary endpoint was the one-year heart failure hospitalizations and secondary endpoints included one year cardiovascular mortality and changes in NT-proBNP, plasma creatinine and glycosylated hemoglobin levels. Results The study shows a significant difference in heart failure hospitalization between the groups. In the Control group, it was 25.8%, and in the Dapa group, it was 8.1% (p = 0.008). Initially, there were no significant changes in NT-proBNP levels; 1152.2 ± 222.4 pg/ml in the Control group and 1197.3 ± 279.8 pg/ml in the Dapa group (p= 0.33). At the end of a year, NT-proBNP increased in the Control group (1827.4 ± 317.8 pg/ml), whereas in the Dapa group, it significantly decreased (613.5 ± 215.6 pg/ml) (p < 0.01). One-year cardiovascular mortality in the Control and Dapa groups was 9.7% and 4.8%, respectively(p=0.491). Other blood markers did not differ, and side effects were comparable during the in-hospital period as well as at the end of the year. Conclusion Early administration of Dapagliflozin among non-diabetic patients with primary anterior STEMI is associated with a significant decreasing of heart failure hospitalization rate and NT-proBNP level. Additionally, early administration of dapagliflozin does not impact on safety indicators.

Real world evidence of Sacubitril/Valsartan in octogenarian patients with heart failure. Results From the PARACHUTE-HF Study

Abstract Introduction The beneficial effects of Angiotensin Receptor Neprilysin Inhibitors (ARNI) on heart failure (HF) patients, particularly those with reduced left ventricular ejection fraction (LVEF), have been highlighted in several randomized controlled trials. Since 2020, ARNI has been available for HF treatment in Japan, a country known for its aging population. However, the inclusion of octogenarians in previous trials has been limited, leaving a gap in evidence regarding ARNI's effectiveness in the elderly. Objective This study aims to explore the real-world efficacy and safety of ARNI treatment among octogenarian HF patients in Japan, reflecting its status as a leading aging society. Methods The Prospective Area Registry of ARNI for Congestive Heart failUre in Tokyo East (PARACHUTE) trial, a multicenter registry, was conducted. It involved patients newly prescribed ARNI for chronic HF regardless of LVEF between 2020 and 2021. We compared patient backgrounds, changes in NT-proBNP levels at 6 months, and the rate of ARNI discontinuation between groups aged below and above 80 years. Results The study enrolled 105 patients, with an average age of 75 years. Forty-six patients (44%) were over 80 years old, and the majority (72%) were male. Among the younger group, 50% had preserved LVEF, compared to 32% in the octogenarian group (p=0.01). Median NT-proBNP levels across all patients decreased significantly from 2,540 pg/mL at baseline to 998 pg/mL at 6 months. The reduction in NT-proBNP was similar between the two age groups, with no significant interaction (p=0.46). Discontinuation rates due to any cause were not significantly different between younger and older patients (7% vs. 13%, p=0.28). Conclusion ARNI treatment resulted in significant reductions in NT-proBNP levels in HF patients, both under and over 80 years of age, with comparable discontinuation rates. These findings highlight the effectiveness and safety of ARNI in the management of chronic HF in the elderly, offering valuable real-world evidence from Japan's unique demographic context.

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

Association of soluble ST2 with heart failure and other comorbidities in patients with severe coronary heart disease

Abstract Background Circulating levels of soluble suppression of tumorigenicity-2 (sST2) reflect vascular congestion, inflammation, and fibrosis. sST2 has been proposed as a useful biomarker to predict the mortality and hospitalization due to heart failure. However, there is limited evidence regarding the relationship between sST2 and heart failure, as well as other comorbidities, in severe coronary heart disease (CAD). Purpose This study aims to measure the circulating levels of soluble ST2 (sST2) in a large population of patients with severe CAD to determine its association with heart failure, cardiac function, inflammation, and other important comorbidities. Methods This subanalysis is part of the ongoing perspective observational study. Available serum samples from 520 patients undergoing elective coronary artery bypass grafting (CABG) were analysed for sST2 levels. The inclusion criteria were written informed consent and age between 18-85 years. Exclusion criteria for this analysis were severe valvular disease, severe chronic obstructive pulmonary disease, oxygen therapy, nocturnal positive airway pressure support or mechanical ventilation, and the need for catecholamines or circulatory assist devices. The circulating levels of human sST2 were measured from frozen serum (-80°C) using commercially available ELISA kits. The plasma was diluted 100 times to detect sST2 levels (assay range of 31.2 - 2,000 pg/mL). Two measurements were taken to account as means for intra-assay variabilities. Logarithmic transformation was used to convert non-normal distributed data. Student t' test and linear regression were applied to categorical or continuous variables as appropriate. Results sST2 levels (median 20.4 ng/ml, [IQR 15.5 – 28.8]) significantly predict worse left ventricular ejection fraction (β = -0.164, p = 0.006), and significantly correlate with levels of NT-proBNP (β = 3.263, p < 0.001), hs-Troponin T (β = 3.391, p < 0.001), high-sensitivity C-reactive protein (β = 2.472, p = 0.014) and heart failure (p= 0.002). Interestingly, common comorbidities such as chronic kidney disease (estimated glomerular filtration rate < 60 mL/min/1.73 m2, p = 0.004), diabetes mellitus (p = 0.001) and higher levels of glycated haemoglobin (HbA1c, β = 3.615, p < 0.001) showed also a significant association with sST2 levels. No significant association of sST2 was observed with arterial hypertension (p = 0.190), atrial fibrillation (p = 0.289), obesity (BMI ≥ 30 kg/m2, p = 0.302), sleep apnoea (apnoea-hypopnoea index ≥ 15/h, p = 0.068), peripheral artery disease (p = 0.823), or previous stroke (p = 0.861). Conclusion(s) Circulating levels of sST2 significantly correlate with heart failure, NT-proBNP, hs-TnT, and hs-CRP in patients with severe CAD. Additionally, sST2 levels were found to be elevated in patients with diabetes mellitus and chronic kidney disease.

Comparison of pulsed field ablation versus cryoballon and radiofrequency ablation for pulmonary vein isolation in atrial fibrillation patients with heart failure

Abstract Background Pulmonary vein isolation (PVI) is the gold standard for atrial fibrillation (AF) ablation and can be achieved by a variety of technical methodes. While thermal ablation modalities (TA), such as cryoballon (CB) and radiofrequency ablation (RF) have been established as the standard approaches, PFA has been introduced as a nvel non-thermal modality showing comparable safety and procedural efficiency. Despite the high incidence of AF in heart failure (HF) patients, data comparing outcomes of HF patients undergoing PVI by either PFA or thermal ablation (RFA/CB) are limited. Purpose This study’s aim was to compare the efficacy and safety of PFA for AF ablation versus CB/RFA in HF patients. Methods Consecutive HF patients with preserved (HFpEF), mildly reduced (HFmrEF) and reduced (HFrEF) ejection fraction undergoing PVI for AF by either PFA or CB/RFA at our institution were included. The primary end-point was time to death or recurrence of AF. Secondary end-points were periprocedural complications and clinical and echocardiographic parameters. Results We included 140 HF patients who underwent PVI either by PFA (PFA group, 76 patients) or thermal ablation approaches (TA group, 64 patients). Our patients had a mean age of 69 years and were predominantly male (62%). There was no significant difference in the baseline characteristics and in the type of AF between both groups (42% with ParAF, 45% with PersAF) and 13% LSPersAF). The distribution of heart failure types was similar between both groups: HFpEF (PFA: 71%, TA: 75%), HFmrEF (PFA: 21%, TA: 20%) and HFrEF (PFA: 8 %, TA: 5%). After the 365-days follow-up period we observed no significant difference for the primary end-point between both groups (HR: 0.79, 95% CI 0.35-1.78; p=0.575). In total 58% of the PFA patients and 59% of the TA group were still free from AF. While symptom improvement was documented in both groups, patients in the PFA group showed significant improvement of left atrial volume index (p = 0.014), NT-pro BNP levels (p = 0.046), and left ventricular ejection fraction (LVEF) (p = 0.005). Conclusion In this study, PFA and thermal ablation modalities showed comparable results in terms of safety and procedural efficiency in patients with heart failure. Since previous studies have shown that HF patients with AF benefit from PVI using thermal ablation modalities, our results suggest that PFA might also be a promising ablation method in this vulnerable population, inducing left atrial reverse remodeling and thereby contributing to improvement of left ventricular systolic function.

Prognostic value of albumin-bilirubin score in patients with chronic heart failure

Abstract Background Liver dysfunction is one of the common comorbidities, and associated with worse clinical outcomes in patients with chronic heart failure (CHF). Recently, the albumin-bilirubin (ALBI) score has been developed as an effective and convenient scoring system for assessing liver function. However, the prognostic significance of the ALBI score in patients with CHF remained to be clarified. Purpose We sought to investigate the clinical significance of ALBI score on outcome prediction in patients with CHF. Methods We prospectively examined 1567 symptomatic CHF patients (median age 74, inter quartile range [IQR] 64-82 years, mean left ventricular ejection fraction [LVEF] 49 ± 15.9 %, median N-terminal pro-brain natriuretic peptide [NT-pro BNP] 801 [IQR 372-1820] pg/ml) in a multicentre registry with 27 Japanese sites between January 2020 and December 2023. The ALBI score was calculated according to the following formula: log10 total bilirubin (mg/dl) × 0.06 + albumin (g/dL) × 10 × (-0.085). Studied patients were divided into three groups according to the ALBI grade; ALBI score ≤ -2.60 (Grade1, n = 691), -2.60 < ALBI score ≤ -1.39 (Grade 2, n = 864), ALBI score > -1.39 (Grade3, n = 12). Primary outcome of interest was a composite of all-cause death and hospitalisation due to worsening heart failure. Results Patient with higher ALBI grade had higher age, New York Heart Association functional class, NT-pro BNP level, prevalence of atrial fibrillation and chronic obstructive pulmonary disease, and lower body mass index, systolic blood pressure, haemoglobin level, serum albumin level and estimated glomerular filtration rate compared to those with lower ALBI grade. LVEF was comparable between the groups. During a median follow-up period of 537 (IQR 285-701) days, the primary outcome occurred in 267 patients (17%). Higher ALBI grade were significantly related to increased incidence of the primary outcome (P for trend < 0.001) (Figure 1). Multivariable Cox regressions showed that a higher ALBI score was independently associated with higher risk of the primary outcome (hazard ratio 2.8, 95% confidential interval (CI) 2.08-3.77, P < 0.001), even after adjustment for the MAGGIC score as an established risk prediction model, NT-pro BNP, aspartate aminotransferase, and platelet counts. Furthermore, addition of the ALBI score to the MAGGIC score significantly increased c-index from 0.70 (95% CI 0.66-0.74) to 0.73 (95% CI 0.69-0.76) (P < 0.001) (Figure 2). The net reclassification improvement afforded by the ALBI score was 26% for the primary outcome (P<0.001). Conclusions Liver dysfunction assessed by the ALBI score was independently associated with worse clinical outcomes in patients with CHF. Moreover, addition of the score to the existing risk prediction model significantly increased the ability of outcome prediction, suggesting beneficial clinical application of the ALBI score in patients with CHF.

An Elevated FIB-4 Score is associated with the severity of heart failure

Abstract Background Liver disease and heart failure (HF) are known to be closely associated. Non-invasive tests (NIT), such as the FIB-4 score, have been recommended by different guidelines to rule out advanced liver fibrosis and to stratify the risk of liver-related outcomes in patients with chronic liver diseases. Purpose Thus, our goal was to evaluate the connection between the FIB-4 index, heart failure, associated comorbidities, and cardiological biomarkers that predict the risk of liver fibrosis in patients with heart failure. Methods HF patients hospitalized in the cardiology department were divided into a group with an FIB-4 index <1.3 (indicating a low risk of liver fibrosis) (n=53) and a group with an FIB-4 index ≥1.3 (indicating intermediate and high risk of fibrosis) (n=59). Clinical examinations, laboratory results, echocardiography with Vivid E95-GE Healthcare, non-invasive body mass analysis with Body Composition Analyzer (Tanita Pro), and measurements of NT-proBNP, growth differentiation factor 15 (GDF-15), galectin-3, fatty acid-binding protein (FABP), copeptin, and vascular endothelial growth factor (VEGF) concentrations were performed. Results The patients with an FIB-4 index ≥1.3 had significantly higher: left ventricular volume index (LAVI) (p=0.004), E/E’ ratio (p=0.004) and lower left ventricular ejection fraction (p=0.003) compared to group with low risk of liver fibrosis. There were no differences in body mass compartments between groups except for ECW/TBW (%) - an index of body water distribution, which was lower in low-risk liver fibrosis group (p=0.0002). Patients with an FIB-4 index ≥1.3 had also lower: GFR MDRD (median 59.95 vs 85.1 mL/min/1.73 m²; p<0.001), total cholesterol (116.5 vs 15 mg/dL; p=0.002), LDL cholesterol (median 56 vs 93 mg/dL; p<0.0001) and HDL cholesterol (median 39 vs 47 mg/dL; p=0.03). Regarding heart failure biochemical biomarkers, patients with low risk of liver fibrosis had significantly lower level of NT-proBNP (median 37 vs 161 pg/ml; p<0.0001), GDF-15 (median 399.6 vs 898.9 pg/ml; p<0.0001) and FABP (median 101 vs 264,7 pg/ml; p=0.04). In a multiple logistic regression model the factors that were independently associated with the risk of liver fibrosis in HF patients based on an FIB-4 index were GDF-15 >724 pg/ml (OR 33.7, 95%CI: 6.5-174.2; p=0.0001), and NT-proBNP >129 pg/ml (OR 19.9, 95% CI: 3.8-103; p=0.0001) (Figure 1) Conclusion Our study suggests association between an elevated FIB-4 score and heart functions, and kidney impairment with fluid overload but not with higher total and low density cholesterols fractions or percentage of fat. Higher GDF-15 and NT-proBNP levels are independently associated with the risk of liver fibrosis based on an FIB-4 index. FIB-4 index in HF patients is an easy method to monitor the risk of liver fibrosis and might help to predict the HF progression and CVD complications.

Combined evaluation of liver and kidney function improves prediction of clinical outcome in patients with chronic heart failure and reduced ejection fraction

Abstract Background/Introduction The liver and the kidneys are important organs for body homeostasis and are both affected by heart failure (HF) either by systemic venous congestion or hypoperfusion. Purpose We aimed to verify whether the Model for End-stage Liver Disease eXcluding International normalized ratio (MELD-XI), as well as a combination of cholestatic liver and kidney function tests carry prognostic value in patients with chronic HF with reduced ejection fraction (HFrEF). The liver parameters included alkaline phosphatase (ALP), gamma glutamyl-transpeptidase (GGT), and total bilirubin, while kidney parameters consisted of eGFR and the tubular damage markers urinary N-acetyl-beta-D-glucosaminidase (NAG) and kidney injury molecule (KIM)-1. Methods We categorized 250 patients with HFrEF on the basis of baseline biomarker levels. We assumed elevated NT-proBNP indicates hemodynamic congestion necessary to induce congestive liver or kidney dysfunction. Thus, in every organ damage category, NT-proBNP level above median was incorporated, next to any 2 out of 3: ALP, GGT or total bilirubin above median for liver dysfunction; any 2 out of 3 NAG or KIM-1 above median or eGFR below median for kidney dysfunction; or coexistence of liver and kidney dysfunction as defined above. Additionally, a subgroup of patients with both NT-proBNP and MELD-XI above the median was analyzed. The primary endpoint was a composite of cardiovascular death, heart transplantation, LVAD implantation, and hospitalization for acute or worsened HF, whichever occurred first. Univariable and multivariable Cox proportional hazard regression models were used. Results Median (Q1-Q3) age of the study population was 68 (58-76) years; 184 (74%) were men, 62 (25%) in NYHA class III or IV, and mean left ventricular ejection fraction (LVEF) was 31±9%. During a median (Q1-Q3) follow-up of 2.2 (1.4-2.5) years, 66 (26%) patients reached the primary endpoint. We observed that liver dysfunction, kidney dysfunction or their coexistence was associated with significantly higher risk of reaching the primary endpoint (HR 3.54, 95% CI 1.75–7.16; HR 1.85, 95% CI 1.00–3.41; HR 2.52, 95% CI 1.03–6.11 respectively) in the clinically adjusted model (Table 1). Higher MELD-XI was associated with higher risk of reaching the primary endpoint in an unadjusted model but not in a clinically adjusted model. Figure 1 presents event-free survival probability of patients falling into organ dysfunction categories. Conclusions Our results show that markers of cholestatic liver function and kidney function predict unfavorable clinical outcome and provide better prognostic value in chronic HFrEF patients than the MELD-XI alone. Thus, screening for liver and kidney damage may help identify high-risk patients in whom more careful observation and individualized therapy is warranted.Fig 1.Event-free survival probability

Enhancing primary prevention: the incremental predictive value of NTproBNP beyond ASCVD risk assessment

Abstract Background Atherosclerotic cardiovascular disease (ASCVD) is a global health challenge, prompting widespread use of conventional risk assessment tools (SCORE2 in Europe and the ASCVD Risk calculator in the United States) to guide preventive strategies. Emerging evidence indicates that NTproBNP may help refine risk stratification. We investigate whether measuring NTproBNP in primary prevention correlates with mortality and enhances prediction compared to conventional risk score stratification. Methods Utilizing National Health and Nutrition Examination Survey (NHANES) data (1999 to 2004) linked to the National Death Index, our cohort included individuals without a history of CVD at baseline and suitable for assessment of the ASCVD ACC/AHA risk score. Individuals were grouped based on computed 10-year risk (low: <5%; borderline: 5-7.5%; intermediate: 7.5-20%; high: ≥ 20%). NTproBNP levels were measured (Roche assay, cut-off > 125pg/mL considered as positive). Cox regression estimated the association between ASCVD risk categories, with or without NTproBNP, and all-cause and cardiovascular mortality. Results Among 5257 adults, 47% male, mean age 54 ± 9.1 years, the mean 10-year ASCVD risk was 8.17 ± 8.2%, grouped as: low: 53.3%; borderline: 11.5%; intermediate: 23.9%; and high: 11.3%. NTproBNP > 125pg/mL was measured in 12.2%, 16%, 23.2% and 48.6% individuals, respectively (p < 0.001). Over 16.2 ± 3.4 years, all-cause and cardiovascular death was 22.3% and 5.6%, respectively. Compared to low-risk, the hazard ratio (HR) for all-cause death increased to 2.85 (2.2-3.7), 5.6 (4.2-7.5), and 15.3 (11.7-19.9) for borderline, intermediate, and high-risk, respectively. A significant interaction with NTproBNP was observed (low: HR 1.96 (1.33-2.9); borderline: HR 2.5 (1.6-3.9); intermediate: HR 2 (1.6-2.6), high: HR 1.7 (1.4-2.2), p<0.01 for all interactions, see Fig. 1). For cardiovascular death, a significant interaction also occurred across the groups, but of higher magnitude in low and borderline groups (low: HR 3.2 (1.4-7.3); borderline: HR 5.5 (2.5-12.4), p < 0.001 for both). Conclusion Our findings suggest that NTproBNP provides incremental predictive value, approximately doubling the hazard of all-cause death across all risk categories, and more than tripling the hazard of CV death in low/borderline risk groups, compared to ASCVD risk alone. The integration of NTproBNP measurements into risk assessment strategies could refine primary prevention approaches.

Efficacy and safety of ambulatory, weekly, high-intensity intravenous diuretic strategy for congestion-refractory heart failure patients: insights from the DEA-HF prospective randomized clinical trial

Abstract Background Congestion and volume overload are strongly associated with low quality of life and pose a significant risk for both rehospitalization and mortality in heart failure (HF) patients. Despite the widespread use of diuretics in HF, the use of weekly, intravenous (IV), high-intensity diuretic treatment has not been prospectively studied in the setting of ambulatory congestion-refractory patients. Purpose To assess the efficacy and safety of weekly high-intensity diuresis regimens in a practical setting of ambulatory day care for chronically congested HF patients. Methods We performed a sub-analysis on data from a prospective, randomized, cross-over controlled study (DEA-HF) originally designed to compare diuresis regimens in the setting of an HF ambulatory daycare unit who had signs of congestion or volume overload despite adherence to guideline-directed medical therapy. Each patient received three different IV diuretic regimens, in one of six randomized sequences: IV furosemide 250mg; IV furosemide 250mg + oral metolazone 5mg; and IV furosemide 250mg + IV acetazolamide 500mg. All regimens given on the same chronological week were pooled, and diuresis efficacy was assessed by measuring excreted urine volume and sodium weight 6 hours post treatment initiation. Additional assessment at one week post each treatment included serum levels of NT-ProBNP, body weight and creatinine as well as congestion score based on the presence of ascites, pleural effusion and pedal edema. Statistical analysis was based on linear mixed models while accounting for the random effect of patient identity. Results A total of 42 patients were recruited. The mean age was 72±9 years, twenty-one subjects (50%) had LVEF ≥ 50%. 74% of patients were NYHA III class. All patients were on contemporary guidelines-directed HF therapy. Analysis of excreted sodium weight and urine volume revealed values of 4202.1±180.1 mg (Mean±SEM) and 1.77±0.07 liter per visit, respectively. No significant differences in efficacy were detected among treatments given in consecutive weeks (P= 0.80 and 0.69 for differences in sodium weight and urine volume, respectively). After 4 weeks, log(NT-ProBNP) was significantly decreased (P=0.044), accompanied by a significant decrease of 2.4±0.62 kg in body weight (P=0.0004) and of 0.92±0.44 points in congestion score (P=0.037). Serum creatinine level was only slightly increased by 0.19±0.04 mg/dl (P=0.0001), demonstrating the overall safety of the high-intensity diuresis strategy. Conclusions In ambulatory, congestion refractory HF patients a strategy based on high-intensity, weekly diuresis therapy was safe and effective for three consecutive weeks. The natriuresis response to the treatments was maintained, NT-ProBNP levels and congestion score were decreased. The strategy may be instrumental for ambulatory HF patients that require diuretic therapy intensification and may allow to prevent hospitalization.