bluuebunny/crossref_metadata_2025_split huggingface dataset:
Trends of phosphorus levels after intravenous administration of ferric carboxymaltose
Authors: Borrellas A , Domingo M , Lupon J , Pulido A , Gonzalez B , Rivas C , Velayos P , Bares D , Diaz V , Crespo E , Martinez S , Codina P , Santiago-Vacas E , Cediel G , Bayes-Genis A 
Published: November 2023

Abstract

Background
Iron deficiency and anaemia are present in a large number of patients with heart failure. Intravenously ferric carboxymaltose (FCM) is the recommended treatment, but it may be associated with hypersensitivity reaction and hypophosphatemia, the later mainly in subjects with normal renal function. The prevalence of hypophosphatemia driven by FCM in patients with heart failure (HF) is not well established.

Purpose
To assess the prevalence and trends of serum phosphorus levels after FCM administration in outpatients with HF.

Methods
Prospective, observational, consecutive, and descriptive study of patients admitted in a HF clinic eligible to receive FCM between January 2022 and June 2022. Phosphorus and calcium homeostasis regulators (magnesium, vitamin D, parathyroid hormone, alkaline phosphatase) were drawn at baseline and after 3 weeks of the infusion. In those patients with documented hypophosphatemia after iron administration, a third measurement was performed at three months from baseline. Paired T-test was used to compare mean values and logistic regression to predict relationship of changes in serum phosphorus with other factors.

Results
101 patients were included (71.5 ± 10.6 years, 31.7% women, LVEF 43.9 ±11.9%, 49.5% of ischaemic aetiology, glomerular filtration rate 39.44 ±10 mL/min/m2). Mean baseline phosphorous was 3.64 ± 0.66 mg/dL, declining to 2.74 ±0.88 mg/dL (p for trend = 0.001). Calcium, magnesium, and vitamin D also showed a post-infusion declining tendency (p = 0.001, p = 0.05 and p= 0.002, respectively), whereas PTH significantly increased (p = 0.015). At three weeks, 38 (37.6%) patients had phosphorous levels below the normal threshold (mean 2.15 ± 0.76 mg/dl), which normalized at three months from baseline (mean 3.12 ±0.77 mg/dl; p = 0.71) without specific treatment. Figure 1 shows phosphorus dynamics of the 38 patients with infusion hypophosphatemia. There was no predicted correlation between FCM dose, glomerular filtration rate and phosphorous trends (p = 0.627, P = 0.234 respectively). No clinical adverse event was reported.

Conclusion
Ferric carboxymaltose infusion in patients with HF is associated with a decline in circulating phosphorous, with 1 in 3 patients showing frank hypophosphatemia. This effect is transient and does not require treatment nor active phosphorus monitoring.Trends of hypophosphatemia
Similar heart failure hospitalization and survival benefits are associated with Sacubitril/Valsartan therapy in CRT non responders and in HFrEF patients with no CRT indication
Authors: Szabo K , Toth A , Racz V , Szuromi L , Nagy L , Barta J , Borbely A , Csanadi Z 
Published: November 2023

Abstract

Background
Sacubitril/Valsartan (S/V) induced reverse remodelling and improved heart failure (HF) hospitalisation and survival in HF with reduced ejection fraction (HFrEF) in recent trials. Data on the clinical effectiveness of S/V in the specific HF patient cohort of CRT non-responders (CRT-NRs) are limited.
Aim of the study: Herein, we compared the impact of S/V on hospitalisation and mortality in CRT-NRs and in HFrEF patients with no CRT indication. In addition, we evaluated the outcome in patients with versus without a more marked response to S/V therapy.

Methods
Database search was performed to identify patients based on the following criteria. Group I: Patients implanted with a CRT pacemaker or ICD who demonstrated a less than 10% increase in left ventricular ejection fraction (LV EF) 6 months after device implantation on optimal medical therapy (CRT-NRs). In addition, these CRT-NRs were initiated on S/V as a replacement of ACEi/ARB therapy at least 6 months after device implantation. Group II: HFrEF patients with no CRT indication initiated on S/V. Patents were on S/V treatment at least for 6 months in both groups. Hospitalization and mortality rates were compared in both groups during follow-up. A subgroup analysis was also performed based on the improvement in LV EF on S/V. Patients with a more than 10% improvement were defined as S/V Super-responders, while those with a less than 10% increase as S/V Moderate responders.

Results
70 patients were enrolled in Group I, and 135 in Group II. During a follow-up of 21.9±1.6 no significant differences were detected in the rates of hospitalization (31% vs 28%; p:0.742) and mortality (18.5% vs 17.2%; p = 0.456) in Group I and II, respectively. In group I, 13 (18.5%), and in Group II, 24 (17.7%) patients were identified as SV Super-responders. Rates of hospitalization were similar in S/V Super-responders and in SV Moderate responders in Group I (23.1% vs 31,6%, p = 0.464) as well as in Group II (25% vs 30.7%, p = 0.602). Mortality rates were similar, alike in in S/V Super-responders and in SV Moderate responders in both groups (Group I:15.4% vs 24.6%, p = 0.320, Group II: 20.8% vs 25.3%, p = 0.789).

Conclusion
Similar hospitalization and mortality rates were demonstrated on S/V in CRT-NR and in HFrEF patients with no CRT indication during a 21-month follow-up. A more than 10% increase of LV EF on S/V treatment did not predict improved hospitalization and survival as compared to a more moderate response in either group.
Statin and risk of dementia in patients with heart failure
Authors: Ren Q W , Chan H C , Tse Y K , Wu M Z , Xu X , Yiu K H 
Published: November 2023

Abstract

Background
Non-cardiovascular morbidity and mortality of heart failure (HF) patients rose immensely in recent years, with dementia emerging as one of the key comorbidities. Our study aims to investigate the association between statin use and the risks of dementia and its subtypes in HF patients.

Methods
104 295 patients with incident HF diagnosis from 2004 to 2018 were identified and followed up until December 2020. Inverse probability of treatment weighting (IPTW) was used to balance baseline covariates between statin users (N = 54004) and non-users (N = 50291). The primary outcomes were incident all-cause dementia, including subtypes of Alzheimer’s disease, vascular dementia, and unspecified dementia. Cox proportional-hazard model with competing risk regression was performed to estimate the sub-distribution hazards ratio (SHR) with corresponding 95% confidence intervals (CI) of the risks of all-cause dementia and its subtypes that are associated with statin use.

Results
Of all eligible HF patients, the mean age was 74.2 ±13.6 years old and 52,511 (50.3%) were male. Over a median follow-up of 9.9 years (interquartile range [IQR]: 6.4 to 13.0), 10,031 (9.6%) patients were diagnosed with dementia, among which Alzheimer's disease (N = 2,250), vascular dementia (N = 1,831), and unspecified dementia (N = 5,950) were quantified separately. After IPTW, statin use was associated with a 20% lower risk of incident dementia compared with non-use (multivariable-adjusted SHR 0.80, 95% CI 0.76 to 0.84). Stratified by subtypes of dementia, statin use was associated with a 27% lower risk of Alzheimer’s disease (SHR 0.72, 95%CI 0.63 to 0.82), 18% lower risk of vascular dementia (SHR 0.82, 95%CI 0.70 to 0.95), and a 20% lower risk of unspecified dementia (SHR 0.80, 95%CI 0.75 to 0.85).

Discussion
In patients with HF, statin use was associated with a significantly lower risk of all-cause dementia and its subtypes, including Alzheimer’s disease, vascular dementia, and unspecified dementia.
Mediators of the benefit of sotagliflozin in patients with worsening heart failure in SOLOIST-WHF
Authors: Szarek M , Bhatt D , Steg P G , Davies M J , Pitt B 
Published: November 2023

Abstract

Background
In SOLOIST-WHF, the dual SGLT1 and SGLT2 inhibitor sotagliflozin (SOTA) reduced primary endpoint events – total occurrences of cardiovascular (CV) death and hospitalizations and urgent visits for heart failure (HF) – by 33% relative to placebo (PBO) among 1222 patients hospitalized for worsening HF. The extent to which treatment group differences in biomarkers assessed during study follow-up contributed to this benefit of SOTA is unknown.

Purpose
The contributions of 20 biomarkers (identified in published mediation analyses of SGLT2 inhibitors: HbA1c; weight; BMI; systolic and diastolic BP; heart rate; serum creatinine, urate, albumin, sodium, and magnesium; eGFR; hematocrit; hemoglobin; erythrocytes; total cholesterol; LDL-C; HDL-C; non-HDL-C; triglycerides) to the reduction of primary endpoint events by SOTA relative to PBO were quantified via mediation analyses to describe the mechanisms of SOTA.

Methods
Patients were randomized 1:1 to SOTA 200 mg/day (with possible increase to 400 mg/day) or PBO and followed for a median 9 months. Two conditions must be met for a biomarker to be a mediator: there had to be a treatment group difference on the biomarker and an association between the biomarker and risk of primary endpoint events. For the first condition, treatment group differences in change from baseline in each biomarker were analyzed by mixed effects repeated measures models. For the second condition, time-varying values of each biomarker were related to the risk of primary endpoint events by calculating the time-weighted moving average (TWMA) for each variable, using all values for a given patient. Each was analyzed in a competing risks marginal model for total events (stratified according to left ventricular ejection fraction at baseline and geographic region of enrollment), in which non-CV deaths were treated as competing terminal events and TWMA values were included as a time-varying covariate. The individual and joint mediation of those biomarkers determined to be mediators were assessed in competing risks marginal models that included treatment assignment. If biomarkers that would otherwise be included in multivariable models were strongly correlated (baseline values R2&gt;0.5), the marker with the greatest univariate mediation was included. All analyses were intention-to-treat.

Results
Among the biomarkers considered, serum urate, hemoglobin, and total cholesterol met the criteria for being mediators. Serum urate was the strongest single mediator, while the joint mediation for these three biomarkers was 22.3% (Figure 1).

Conclusion
In SOLOIST-WHF, a fraction of the benefit of SOTA was attributable to effects on biomarkers accounting for most of the treatment benefits of other SGLT2 inhibitors on CV death and HF events. Further investigation is therefore needed to identify what unique biomarker treatment effects might account for the majority of SOTA benefit.Figure 1
Safety, tolerability, and pharmacokinetics of AZD5462, a small molecule agonist of the RXFP1 relaxin receptor
Authors: Rosenmeier J , Connolly K , Matsson E , Astrand M , Althage M , Pettersen D , Whittaker A , Turton M , Kujacic M , Gabrielsen A 
Published: November 2023

Abstract

Introduction
Despite multiple new drug advancements for patients with heart failure in recent years (specifically, sodium-glucose co-transporter-2 and sacubitril/valsartan), morbidity and mortality remain high. AZD5462 is a selective RXFP1 agonist which mimics the pregnancy hormone relaxin and its actions on systemic hemodynamics and kidney function.

Purpose
To assess the safety, tolerability, and pharmacokinetics (PK) of AZD5462 in a first-in-human study following single ascending dose (SAD) and multiple ascending dose (MAD) administration in healthy participants.

Methods
This was a phase 1 randomized, double-blind, placebo-controlled study. The SAD evaluated doses of 20, 80, 400, 750, and 1000 mg across 7 cohorts, with 2 cohorts comprising solely participants of Japanese descent. The MAD evaluated doses of 40, 120, 250, and 500 mg BID for 10 days across 5 cohorts, with 1 cohort of Japanese descent. There were approximately 8 participants in each cohort, randomized 6:2 to AZD5462 or placebo. AZD5462 was administered as an oral liquid solution.

Results
Overall, 98 participants were randomized and 92 completed the study (56 of 56 in SAD; 36 of 42 in MAD). The majority of participants randomized were male, and the median age was 39 years in the SAD and 36 years in the MAD. There were no major safety and tolerability concerns up to the highest dose administered (1000 mg SAD; 500 mg BID MAD). Pre-specified study stopping criteria were not met. There were no deaths or other serious adverse events. AEs were more common in the pooled AZD5462 group than placebo (approximately 40% for AZD5462 and 20% for placebo). The most common AEs were GI disorders (nausea, abdominal pain, vomiting), headache, medical device site dermatitis, and orthostatic heart rate response increase, but without clear relationship to dose. Three participants discontinued the MAD due to dizziness, supraventricular tachycardia, and positive COVID-19 test. There was no clear pattern in the effect on SBP with 120 mg and higher doses in the MAD. There was a trend for DBP decrease but no signs of hypotension. HR increased in all cohorts, which was dose-dependent in SAD but without clear relationship to dose in MAD. Treatment with AZD5462 led to a dose-dependent increase in plasma renin in all but the lowest SAD dose. AZD5462 was rapidly absorbed with a median Tmax between 0.53 hr and 1.75 hr. Plasma concentrations declined in a biphasic manner, with a geometric mean terminal half-life after a single dose between 3 h and 6 h. The exposure to AZD5462 increased more than proportionately with dose.

Conclusions
AZD5462 was generally well tolerated at all dose levels in this phase 1 study. These data pave the way for development of a chronic oral relaxin therapy for patients with heart failure.
Heart rate reduction and outcomes in heart failure outpatients
Authors: Memenga F , Rybczynski M , Gossling A , Kirchhof P , Kondziella C , Fluschnik N , Blankenberg S , Berisha F , Bernadyn J , Bremer W , Becher M , Magnussen C , Knappe D 
Published: November 2023

Abstract

Aim
Pharmacologic reduction of heart rate (HR) with beta blockers (BB) and/or ivabradine has been associated with improved survival in patients with heart failure (HF) in sinus rhythm. We analyzed the impact of different HR-reducing drug treatments on outcomes in a cohort of outpatients with heart failure (HF).

Methods
Consecutive patients with HF and sinus rhythm (SR) referred to a specialized tertiary HF service offering advanced therapy options including assist device and heart transplantation were prospectively enrolled from August 2015 until March 2018. Clinical characteristics were assessed at baseline. We performed Cox regression analyses to examine the effect of the resting HR and the drug regimen (BB in submaximal dose [group 1], BB in maximum tolerated dose [group 2], or BB in maximum tolerated dose plus ivabradine [group 3]) on all-cause mortality and a combined, disease-related endpoint of "death from any cause or heart transplantation".

Results
Of 278 patients included, 213 (76.6%) were male. Median age was 57.0 years (interquartile range 49.0-66.1). HF was due to non-ischemic origin in 167 patients (60.1%). HFrEF was present in 185 patients (73.7%). There was a decent use of guideline-recommended HF medication (MRA in 82%, RAS blocker [ARNI/ACEI/ARB] in 97%). Most patients received treatment with a BB in submaximal [n = 118, group 1], or maximum tolerated dose [n = 136, group 2]. Patients treated with BB in maximum tolerated dose plus ivabradine [n = 24, group 3] were younger (53.0 vs. 58.0 years) and had a lower left-ventricular ejection fraction on echocardiography (EF, 25 vs. 31%) than those without ivabradine.
Over a mean follow-up period of 3.1 years, 30 patients died, and 11 underwent heart transplantation. Upon regression analyses, higher resting HR was associated with an increased risk of death or heart transplantation (hazard ratio HR 1.03 [1.01, 1.06], p = 0.0072, even after adjusting for age and sex. Neither the type of heart rate-reducing therapy (BB with or without ivabradine), nor the dose of BB or ivabradine affected outcome.

Conclusion
Our prospective study underlines the importance of heart rate reduction in HF with SR but failed to demonstrate a better risk reduction in patients with up-titrated BB doses or on a combination of BB plus ivabradine.Study profileKM-curves for the composite endpoint
Effect of sodium-related glucose transporter 2 -Inhibitors on exercise capacity in heart failure patients with reduced ejection fraction, does etiology matter?
Authors: Coppo E , Giraldez Valpuesta A , Gamaza Chulian S 
Published: November 2023

Abstract

Introduction
Recently sodium-related glucose transporter 2 (SGLT2) inhibitors were found to improve cardiovascular outcomes significantly, however their effects on exercise capacity are yet unclear.

Aim
To assess in patients with heart failure with reduced ejection fraction (HFrEF), if etiology may have a role in treatment response to SGLT2-I and exercise improvement.

Methods
We included patients with a recent diagnosis of HF with ejection fraction ≤ 40%, between June 2014 and September 2022. An exhaustive initial evaluation was performed with laboratory tests, echocardiography, and exercise tolerance test, performing a 6-minute-walking test (6MWT). Patients were reassessed after 6 months, prior treatment optimization. Finally, patients were divided according to the HF etiology into ischemic and non-ischemic, comparing the results between the patients who received SGLT2-i and those who did not.

Results
Among the 462 patients included (275 non-ischemic and 187 ischemic; mean age 64.1 ±14.0 vs 61.9 ± 19.8 years, women 27.5% vs 15.8%), 45 and 41 patients respectively, received treatment with SGLT2-i. In both groups, patients who received SGLT2-i, had a significant higher prevalence of hypertension, dyslipidemia, and diabetes mellitus (Non-ischemic: hypertension 68.9 % vs 50.9%, p = 0.02; dyslipidemia 42.2% vs 25.8%, p= 0.02; diabetes mellitus 55.6% vs 28.3 %, p &lt;0.001; Ischemic: hypertension 68.3% vs 50.3%, p = 0.04, dyslipidemia 75.6% vs 47.9, p&lt; 0.02, diabetes mellitus 78% vs 38.4% p&lt;0.001) and were as well treated with ARNI on a higher percentage (Non-ischemic 35.6% vs 13.9% p&lt; 0.001, Ischemic: 39% vs 17.8%, p = 0.004). In the non-ischemic group, patients treated with SGLT2-i had a higher mean age (68.2±12.2 vs 63.3±14.3; p = 0.03). No other differences were observed between the baseline characteristics and the treatment. Treatment with SGLT2-i improved performance in 6MWT (+32.5 m [95% CI 10.7-54.4]) only in non-ischemic group while no differences have been found in ischemic patients.

Conclusions
Treatment with SGLT2-inhibitors has been associated with an improvement in exercise ability at six months only in patients with HFrEF of non-ischemic etiology whereas in patients with ischemic etiology it has not shown improvement in functional capacity. Our study suggests that, in clinical setting, non-ischemic patients may have a greater benefit with SGLT2-inhibitors treatment in term of exercise capacity.
Acoramidis produces near-complete TTR stabilization in blood samples from patients with variant transthyretin amyloidosis that is greater than that achieved with tafamidis
Authors: Ji A , Wong P , Judge D P , Graef I A , Fox J , Sinha U 
Published: November 2023

Abstract

Introduction
Transthyretin (TTR) amyloidosis (ATTR) is a progressive, fatal disease caused by destabilizing TTR variants (TTRv) and age-related factors. Dissociation of tetrameric TTR initiates protein misfolding, aggregation, and tissue deposition which constitutes the mechanism of disease. More destabilizing variants drive more severe clinical phenotypes. TTR stabilizers have demonstrated clinical benefits for neuropathic and cardiovascular outcomes correlated with the extent of TTR stabilization. Acoramidis (AG10) is a novel TTR stabilizer in development for the treatment of TTR amyloid cardiomyopathy.
Hypothesis: Acoramidis achieves near-complete in vitro TTR stabilization, exceeding levels achieved with clinically relevant concentrations of tafamidis (a TTR stabilizer in clinical use), when added to blood samples from ATTRv patients across a spectrum of destabilizing TTR variants.

Methods
Two established assays assessed TTR stabilization: fluorescent probe exclusion (FPE; measures binding site occupancy), and Western blot (WB; quantifies tetrameric TTR persistence under conditions of accelerated dissociation). Over 60 individual patient samples representing 18 unique TTRv across a spectrum of intrinsic instability and clinical phenotypes were assayed. Acoramidis was added at its target clinical trough concentration (10 µM) and compared to tafamidis added at its clinical peak (26 µM) and trough (16 µM) concentrations reported for its maximal approved dose.

Results
Acoramidis bound serum TTR to a greater extent (103 ± 13%) than either peak (87 ± 14%) or trough (71 ± 14%) concentrations of tafamidis. WB assays showed that addition of acoramidis resulted in significantly greater and more durable TTR stabilization (93 ± 14%) than adding tafamidis (peak: 49 ± 14%, trough: 36 ± 13%) in all paired individual patient plasma samples tested (Figure 1, p &lt; 0.0001). Rare variants (A97S, D38A, F64L, L58H, P24S, Y114C) also demonstrated near complete stabilization upon in vitro addition of acoramidis.

Conclusions
At its target therapeutic trough concentration, acoramidis achieved near-complete TTR stabilization across 18 unique genotypes; in the subset of paired samples, the stabilization was significantly greater for acoramidis than for tafamidis even at its peak clinical concentration. This observation held across a range of destabilizing mutations, including a∼2-fold greater stabilization than tafamidis for the prevalent cardiomyopathic V122I variant. Based on the mechanism of disease and the association between TTR destabilization and severity of clinical outcomes, these data suggest that acoramidis has the potential to be a clinically differentiated and efficacious treatment option for patients with ATTRv, independent of variant genotype.