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.

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.

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.