Balcinrenone plus dapagliflozin in patients with heart failure and chronic kidney disease: Results from the phase 2b MIRACLE trial.

AIMS: Many patients with heart failure (HF) have chronic kidney disease (CKD) and may not tolerate mineralocorticoid receptor antagonists. We investigated the efficacy and safety of the novel mineralocorticoid receptor modulator balcinrenone in combination with dapagliflozin in a phase 2b study. METHODS AND RESULTS: From January 2021 to October 2023, we randomized 133 adults with symptomatic HF, ejection fraction <60%, estimated glomerular filtration rate (eGFR) ≥30 to ≤60 ml/min/1.73 m2 and urinary albumin-to-creatinine ratio (UACR) ≥30 to <3000 mg/g, to receive balcinrenone 15, 50 or 150 mg/day plus dapagliflozin 10 mg/day, or dapagliflozin 10 mg/day plus placebo, for 12 weeks. Enrolment was stopped early because of slow recruitment. Relative reductions in UACR from baseline to week 12 (primary endpoint) were not significantly different between the balcinrenone plus dapagliflozin groups versus dapagliflozin plus placebo. There was no clear balcinrenone dose-response relationship. There were possible dose-dependent increases in serum potassium levels, reduced eGFR in the highest dose group, and non-significant trends towards reduced N-terminal pro-B-type natriuretic peptide levels. Hyperkalaemia adverse events led to discontinuation in two participants receiving balcinrenone plus dapagliflozin and none in those receiving dapagliflozin plus placebo. CONCLUSION: While the smaller than planned sample size limits interpretation, we did not see significant reduction in UACR in patients treated with balcinrenone plus dapagliflozin compared with dapagliflozin plus placebo.

Mass Balance and Absorption, Distribution, Metabolism, and Excretion Properties of Balcinrenone following Oral Administration in Combination with Intravenous Microtracer in Healthy Subjects.

An absorption, distribution, metabolism, and excretion study was performed to determine the basic pharmacokinetic parameters, mass balance, and metabolite profiles of balcinrenone, a mineralocorticoid receptor modulator, in humans. This open-label, single-center, nonrandomized study had a two-period design. In period 1, eight healthy male subjects were dosed with a microtracer intravenous infusion of [14C]balcinrenone shortly after receiving an oral dose of unlabeled balcinrenone in a capsule. Following a 7-day washout, the same group of subjects subsequently received an oral dose of [14C]balcinrenone as a suspension in period 2. Clearance and absolute bioavailability of balcinrenone were determined to be 14.2 l/h and 52%, respectively. Renal clearance was determined to be 5.4 l/h (>fu • glomerular filtration rate), indicating elimination via active tubular secretion, which was potentially mediated by P-glycoprotein 1 and/or organic anion transporter 3, according to in vitro transporter data. In total, 94.1% of the oral dose was recovered: 45.2% in the urine and 48.9% in the feces. Balcinrenone was primarily metabolized via oxidation, and in vitro data suggest that cytochrome P450 3A4 was the main enzyme responsible. Intact [14C]balcinrenone accounted for 55% of drug-related material in the plasma; four metabolites were identified, each representing <6% of the total plasma radioactivity. In conclusion, this two-period study has determined the basic pharmacokinetic parameters of balcinrenone in humans, including absolute bioavailability and disposition. No metabolites warranted further evaluation on account of their low representation, and any contribution to the pharmacodynamic response or potential drug-drug interactions was deemed negligible. SIGNIFICANCE STATEMENT: This study provides a detailed understanding of the pharmacokinetics, disposition, and metabolism of balcinrenone following oral and microtracer intravenous administration in humans. In vitro phenotyping and transporter data granted mechanistic insights into the absorption, distribution, metabolism, and excretion properties of balcinrenone. This knowledge will guide future nonclinical and clinical studies evaluating drug-drug interactions, organ dysfunction, and safety of metabolites.

Rationale and design of ENDEAVOR: A sequential phase 2b-3 randomized clinical trial to evaluate the effect of myeloperoxidase inhibition on symptoms and exercise capacity in heart failure with preserved or mildly reduced ejection fraction.

AIMS: Mitiperstat (formerly AZD4831) is a novel selective myeloperoxidase inhibitor. Currently, no effective therapies target comorbidity-induced systemic inflammation, which may be a key mechanism underlying heart failure with preserved or mildly reduced ejection fraction (HFpEF/HFmrEF). Circulating neutrophils secrete myeloperoxidase, causing oxidative stress, microvascular endothelial dysfunction, interstitial fibrosis, cardiomyocyte remodelling and diastolic dysfunction. Mitiperstat may therefore improve function of the heart and other organs, and ameliorate heart failure symptoms and exercise intolerance. ENDEAVOR is a combined, seamless phase 2b-3 study of the efficacy and safety of mitiperstat in patients with HFpEF/HFmrEF. METHODS: In phase 2b, approximately 660 patients with heart failure and ejection fraction >40% are being randomized 1:1:1 to mitiperstat 2.5 mg, 5 mg or placebo for 48 weeks. Eligible patients have baseline 6-min walk distance (6MWD) of 30-400 m with a <50 m difference between screening and randomization and Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TSS) ≤90 points at screening and randomization. The dual primary endpoints are change from baseline to week 16 in 6MWD and KCCQ-TSS. The sample size provides 85% power to detect placebo-adjusted improvements of 21 m in 6MWD and 6.0 points in KCCQ-TSS at overall two-sided alpha of 0.05. Safety is monitored throughout treatment, with a focus on maculopapular rash. In phase 3 of ENDEAVOR, approximately 820 patients will be randomized 1:1 to mitiperstat or placebo. CONCLUSION: ENDEAVOR is the first phase 2b-3 study to evaluate whether myeloperoxidase inhibition can improve symptoms and exercise capacity in patients with HFpEF/HFmrEF.

A Feasibility Study of the DyeVert™ Plus Contrast Reduction System to Reduce Contrast Media Volumes in Percutaneous Coronary Procedures Using Optical Coherence Tomography.

OBJECTIVE: To evaluate the feasibility of using the DyeVert™ Plus EZ Contrast Reduction System in optical coherence tomography (OCT)-guided percutaneous coronary intervention (PCI) procedures and to assess OCT image quality. BACKGROUND: OCT is employed as a powerful intravascular imaging modality; however, it requires blood displacement via contrast injection during image acquisition, thereby posing risk of nephrotoxicity. The DyeVert System is designed to reduce and facilitate monitoring of contrast media volume (CMV) delivered, without diminishing image quality. METHODS: We conducted a prospective clinical feasibility study to determine whether the DyeVert System is non-inferior to manual contrast injection in reducing CMV without lessening image quality during OCT-guided PCI procedures. Eligible participants were ≥ 18 years of age, indicated for coronary OCT, and able to provide informed consent. The primary endpoint was CMV saved during angiography; the secondary endpoint was image quality as evaluated by operators in real time and by an independent core laboratory that also assessed images from a control group that underwent comparable procedures performed without the DyeVert System. RESULTS: Fourteen participants underwent 15 coronary OCT procedures using the DyeVert System. Mean age among participants was 67 ± 11 years, and 11 (78%) were male. Mean eGFR was 71 ± 20 mL/min/1.73m2. Mean attempted CMV administration was 342.01 ± 129.8 mL; mean CMV delivered was 216.21 ± 88.87 mL, representing CMV savings of 37.5 ± 5.3%. Results from quantified OCT analysis suggest that the clear region of interest (ROI) in the DyeVert group was non-inferior (p < .0001) to the control group. There were no device-related adverse events. CONCLUSIONS: The DyeVert™ Plus EZ Contrast Reduction System reduced CMV and preserved an image quality that was non-inferior to OCT-guided PCI procedures without using the contrast reducing device.

An assessment of the quality of optical coherence tomography image acquisition.

Optical coherence tomography (OCT) provides excellent image resolution, however OCT optimal acquisition is essential but could be challenging owing to several factors. We sought to assess the quality of OCT pullbacks and identify the causes of suboptimal image acquisition. We evaluated 784 (404 pre-PCI; 380 post-PCI) coronary pullbacks from an anonymized OCT database from our Cardiovascular Imaging Core Laboratory. Imaging of the region-of-interest (ROI-lesion or stented segment plus references) was incomplete in 16.1% pullbacks, caused by pullback starting too proximal (63.7%), inappropriate pullback length (17.1%) and pullback starting too distal (11.4%). The quality of image acquisition was excellent in 36.3% pullbacks; whereas 4% pullbacks were unanalyzable. Pullback quality was most commonly affected by poor blood displacement from inadequate contrast volume (27.4%) or flow (25.6%), followed by artifacts (24.1%). Acquisition mode was 'High-Resolution' (54 mm) in 74.4% and 'Survey' (75 mm) in 25.6% of cases. The 54 mm mode was associated with incomplete ROI imaging (p = 0.020) and inadequate contrast volume (p = 0.035). We observed a substantial frequency of suboptimal image acquisition and identified its causes, most of which can be addressed with minor modifications during the procedure, ultimately improving patient outcomes.

Predicted Coronary Occlusion and Impella Salvage During Valve-in-Valve Transcatheter Aortic Valve Replacement.

We describe an interesting case of a 71 years old fragile female, with progressive shortness of breath on exertion and ankle swelling, cardiac failure NYHA class III. She also had chest irradiation due to Hodgkin's disease many years before, previous surgical aortic valve replacement using bioprosthetic stent-less Freestyle #25 mm valve (Medtronic, Inc) in 2000 for severe aortic stenosis, history of cardiac arrest in 2012 and angioplasty to ostial RCA, PCI to ostial RCA in 2014, CABG (RA graft to RCA) in 2014 (RCA intra-stent restenosis with refractory ischemia), anemia requiring regular transfusions, bronchiectasis and chronic kidney disease. Because of the great comorbidities, STS 4.9% and worsening of the symptoms due to severe aortic valve regurgitation, heart team decided to perform "valve-in-valve" Transcatheter Aortic Valve Replacement (VIV-TAVR), but we already predicted coronary occlusion while performing this procedure because of the low left main coronary ostium and short aortic valve sinus. So regarding the probable left main coronary occlusion during the valve implantation, we decided to perform the placement of a not deployed stent inside the left main prior to the valve procedure, and to deploy it in case the predicted left main occlusion occurred. So just after the VIV-TAVR procedure, we observed left main coronary occlusion and the patient got ischemic cardiogenic shock and cardiac arrest, so we performed immediate PCI and deployed the bailout stent. After some minutes of chest compressions, an Impella mechanical circulatory support system (Abiomed, Danvers, MA) had to be installed. Patient recovered spontaneous circulation, and after hemodynamic stabilization, she was sent to the Intensive Coronary Unit, without further complications. She was discharged successfully without neurological or cardiac sequelae after 1 week.

Feasibility of coronary angiogram-derived vessel fractional flow reserve in the setting of standard of care percutaneous coronary intervention and its correlation with invasive FFR.

BACKGROUND: Vessel Fractional Flow Reserve (vFFR), a new angiography-derived method for the functional assessment of coronaries, was recently shown to have good correlation with invasive wire-derived FFR, when vFFR-specific image acquisition requirements were followed. We sought to investigate the feasibility of vFFR analysis and its correlation with FFR in the situation where angiography is completed in routine fashion, without intention for virtual analysis. METHODS: Utilizing an anonymized database maintained at our Cardiovascular Imaging Core Laboratory, we included angiographic images from patients that underwent pre- and post-PCI FFR. CAAS Workstation 8.1 software (Pie Medical Imaging) was used for vFFR evaluation. RESULTS: Out of 624 angiograms (312 pre-PCI and 312 post-PCI), vFFR was successfully analyzed in 219 (35.1%) (115 pre-PCI and 104 post-PCI). Reasons for vFFR analysis failure were: <2 angiographic projections (42.5%), table movement while acquisition (25.7%) and resolution incompatibility (15%). From 115 patients with analyzable pre-PCI vFFR, 74 (64.3%) showed agreement with the respective FFR results in terms of positive (≤0.80) vs negative (>0.80) FFR. Pearson's correlation coefficient between them was 0.449 (p < 0.0001). From 104 lesions with analyzable post-PCI vFFR, 94 had availability of FFR, 74 (78.7%) of which showed agreement between the vFFR and FFR. Pearson's correlation between the values was 0.115 (p = 0.2703). CONCLUSION: vFFR could be analyzed in about one-third of previously completed angiographies and a weak correlation was seen between vFFR and FFR. Our results show the importance of following the pre-specified requirements for vFFR analysis. Further studies are needed to validate the software in different settings.

Myocardial velocities, dynamics of the septum primum, and placental dysfunction in fetuses with growth restriction.

INTRODUCTION: Diastolic dysfunction may occur in fetuses with intrauterine growth restriction (IUGR) and may be assessed by myocardial tissue Doppler (MTD). We previously have shown that excursion index of the septum primum (EISP) is reduced in IUGR fetuses over 30 weeks because of a higher left atrial pressure. PATIENTS, SETTING, AND DESIGN: The sample was made up of 14 fetuses with IUGR. MTD examination was carried out with the sample volume placed at the basal lateral wall of the left ventricle (LV), interventricular septum (IVS), and free wall of the right ventricle (RV) to determine E'/A' ratios. EISP was calculated as the ratio between the maximal excursion of the septum primum into the left atrium during diastole and the maximal diastolic diameter of the left atrium. Mitral and tricuspid flows were assessed by the conventional Doppler method. OUTCOME MEASURES: Pearson's correlation test was used to analyze the correlations between the parameters. RESULTS: A positive correlation was observed between UARI and E'/A' ratios for RV (r = 0.63, P = .02), IVS (r = 0.59, P = .03), and LV (r = 0.41, P = .15). There was a negative correlation between EISP and IVS E'/A' ratios (r = -0.58, P = .03), and a positive correlation for LV (r = 0.49, P = .08). At the RV position, a weak negative correlation was observed (r = -0.32, P = .26). CONCLUSIONS: A higher left atrial pressure in fetuses with IUGR, indicated by the lower mobility of the septum primum, is accompanied by higher ratios between early and late diastolic myocardial velocities. Placental dysfunction was correlated to septal E'/A' ratios. Fetal MTD can be a useful method to assess severity of placental dysfunction and fetal distress.

Fetal ductal constriction caused by maternal ingestion of green tea in late pregnancy: an experimental study.

OBJECTIVES: The aim of this study was to test the hypothesis that experimental maternal intake of green tea in late pregnancy causes fetal ductus arteriosus constriction, probably because of prostaglandin inhibition. METHODS AND RESULTS: Twelve fetal lambs (pregnancy > 120 days) were assessed before and after maternal administration of green tea (n = 8) or water (n = 4; controls) as the only source of liquid. After 1 week, echocardiography showed signs of constriction of the ductus arteriosus in all fetuses from mothers ingesting green tea, with increase in mean systolic velocity(from 0.70 ± 0.19 m/s to 0.92 ± 0.15 m/s, 31.4%, p = 0.001) and mean diastolic velocity (0.19 ± 0.05 m/s to 0.31 ± 0.01 m/s, 63.1%, p < 0.001), decrease of pulsatility index (2.2 ± 0.4 to 1.8 ± 0.3, 22.2%, p = 0.003) and increase of mean right ventricular/left ventricular diameter ratio (0.89 ± 0.14 to 1.43 ± 0.23, 60.6%, p < 0.001). In the four control fetuses, there were no significant changes. All lambs exposed to green tea also showed at autopsy dilated and hypertrophic right ventricles, which was not present in control fetuses. Histological analysis showed a significantly larger mean thickness of the medial avascular zone of the ductus arteriosus in fetuses exposed to green tea than in controls (747.6 ± 214.6 µm vs 255.3 ± 97.9 µm, p < 0.001). CONCLUSIONS: This study in fetal lambs shows a cause and effect relationship between experimental maternal exposure of green tea and fetal ductus arteriosus constriction in late pregnancy.

Aortic isthmus blood flow in fetuses of diabetic mothers.

OBJECTIVE: To test the hypothesis that the aortic isthmus flow index (IFI) is lower in fetuses of diabetic mothers than in fetuses of nondiabetic mothers. STUDY DESIGN: We performed a cross-sectional observational study to assess the IFI in fetuses, with (n = 13) and without (n = 37) myocardial hypertrophy, of mothers with diabetes mellitus and in fetuses of nondiabetic mothers (n = 23). Analysis of variance and Tukey test were used to assess differences among the groups. RESULTS: There were no differences in maternal or gestational age among the groups. In fetuses of diabetic mothers, the mean IFI in fetuses with myocardial hypertrophy was 1.19 ± 0.06, and in fetuses without it was 1.18 ± 0.09. The mean IFI in fetuses of nondiabetic mothers was 1.32 ± 0.07 (P < 0.001). CONCLUSIONS: The IFI in fetuses of diabetic mothers is lower than in fetuses of nondiabetic mothers, possibly as a result of a decreased left ventricular compliance.