Effect of Renal Impairment on Pharmacokinetics and Safety of Ensitrelvir, a SARS-CoV-2 3CL Protease Inhibitor.

INTRODUCTION: Ensitrelvir, a novel oral inhibitor of 3C-like protease of SARS-CoV-2, shows efficacy and safety in participants with mild to moderate COVID-19. Since urinary recovery of ensitrelvir ranged from 12.9% to 21.8% across dose groups given 20-1000 mg in a single-ascending dose study, renal excretion contributes to the elimination of ensitrelvir. Therefore, the effect of renal impairment on the pharmacokinetics and safety of ensitrelvir needed to be evaluated. METHODS: This study (NCT05363215) was a phase 1, open-label, nonrandomized, parallel-group study. The effect of renal function on the pharmacokinetics of ensitrelvir was investigated. Ensitrelvir was administered as a single dose of 375 mg to participants with normal renal function and those with mild, moderate, and severe renal impairment. The participants with normal renal function were matched to each participant with moderate renal impairment with respect to sex, age, and body mass index. The unbound fractions in plasma after administration of ensitrelvir were also evaluated. For the safety assessment, the nature, frequency, and severity of treatment-emergent adverse events were evaluated and recorded. RESULTS: The plasma concentrations of participants with renal impairment were higher than those of participants with normal renal function. The ratios (90% confidence intervals) of the area under the plasma concentration-time curve from 0 to infinity (AUC0-inf) in participants with mild, moderate, and severe renal impairment compared to normal renal function were 1.4374 (1.1716-1.7636), 1.4885 (1.1883-1.8646), and 1.6021 (1.2782-2.0080), respectively. The plasma protein-unbound fraction was similar regardless of the plasma ensitrelvir concentration or renal function. Ensitrelvir was well tolerated in participants with mild to severe renal impairment and normal renal function. CONCLUSION: Ensitrelvir was well tolerated by participants with renal impairment. There was no clinically meaningful increase on exposure to ensitrelvir in participants with renal impairment, indicating that no dose adjustment would be required due to renal function.

Intravascular Brachytherapy for the Management of Repeated Multimetal-Layered Drug-Eluting Coronary Stent Restenosis.

BACKGROUND: Because of the widespread acceptance of percutaneous coronary intervention with drug-eluting stents as an effective treatment strategy for in-stent restenosis, it is common to encounter multimetal layer stent restenosis in the recent years. This study aimed to evaluate the clinical outcomes of such patients treated with intravascular brachytherapy (IVBT) in comparison with other percutaneous options. METHODS AND RESULTS: We enrolled patients who underwent percutaneous coronary intervention during the period between 2011 and 2015 for recurrent drug-eluting stents in-stent restenosis with at least 2 layers of stents at the lesion site. This analysis compared patients who underwent treatment with IVBT and those who did not (non-IVBT group). The primary end point measured was major adverse cardiac events defined as a composite of target lesion revascularization, myocardial infarction, and all-cause mortality at 12 months. Adjusted associations were measured using propensity score matching. A total of 328 percutaneous coronary intervention patients met the eligibility criteria, of which 197 patients received IVBT, and 131 patients underwent routine percutaneous intervention. The primary end point was significantly lower in patients undergoing IVBT (13.2% and 28.2%; P=0.01). A propensity score matching for risk factors of in-stent restenosis identified 182 patients. The advantages of IVBT with regard to 1-year major adverse cardiac events were confirmed in this matched cohort (13.2% and 30.8%; adjusted hazard ratio [95% CI]: 0.37 [0.18-0.73]; P<0.01). CONCLUSIONS: In this analysis, IVBT led to significantly lower major adverse cardiac events in patients with multilayered drug-eluting stents restenosis when compared with other percutaneous options at 1-year follow-up.

Clinical and angiographic predictors of haemodynamically significant angiographic lesions: development and validation of a risk score to predict positive fractional flow reserve.

AIMS: Coronary revascularisation based upon physiological evaluation of lesions improves clinical outcomes. Angiographic or visual stenosis assessment alone is insufficient in predicting haemodynamic stenosis severity by fractional flow reserve (FFR) and therefore cannot be used to guide revascularisation, particularly in the lesion subset <70%. Accordingly, we sought to identify independent determinants of angiographic intermediate lesions with haemodynamic significance. METHODS AND RESULTS: We assessed consecutive intermediate lesions for patients from January 2014 to April 2015 at our institution. Independent predictors of FFR positivity (FFR ≤0.8) were identified and a scoring system formulated. Of 1,023 consecutive lesions (883 patients), 314 (31%) were haemodynamically significant. Characteristics associated with FFR ≤0.8 include male gender, higher SYNTAX score, lesions ≥20 mm, stenosis >50%, bifurcation, calcification, absence of tortuosity and smaller reference diameter. A user-friendly integer score was developed with the five variables demonstrating the strongest association. On prospective validation (in 279 distinct lesions), the increasing value of the score correlated well with increasing haemodynamic significance (C-statistic 0.85). CONCLUSIONS: We identified several clinical and angiographic characteristics and formulated a scoring system to guide the approach to intermediate lesions. This may translate into cost savings. Larger studies with prospective validation are required to confirm our results.

Plaque morphology predictors of side branch occlusion after provisional stenting in coronary bifurcation lesion: Results of optical coherence tomography bifurcation study (ORBID).

OBJECTIVES: The aim of this study was to identify the predictors of side branch (SB) ostial stenosis developed after provisional stenting of the main vessel (MV) using optical coherence tomography (OCT). BACKGROUND: Provisional stenting remains the main approach to treatment of bifurcation lesions; however, it may result in the narrowing of SB ostium. There is little information about underlying plaque morphology of the MV lesion and its potential impact on the SB after provisional stenting. METHODS: Patients with stable coronary disease with angiographic MV lesion not involving SB were included in a prospective single center study. The primary outcome was significant SB ostium stenosis (SBOS), defined as residual stenosis of >50% after MV stenting. RESULTS: Thirty bifurcation lesions in 30 patients were analyzed in the study. Poststenting significant SBOS was observed in 30% of patients. The MV lesions with SBOS > 50% were characterized by a higher prevalence of lipid rich plaques (100 vs. 64%, p = 0.040) and spotty calcifications (60 vs. 0%, p = 0.005). Maximal lipid arcs were greater (257° vs. 132°, p = 0.001) and lipid volume index was higher (1380 vs. 574, p = 0.012) in the SBOS >50% group. Multivariate logistic regression analysis identified maximal lipid arc (odds ratio (OR): 1.014, p = 0.038) and the presence of lipid plaque contralateral to SB ostium (OR: 8.14, p = 0.046) before stenting as independent predictors of significant SBOS after PCI. CONCLUSIONS: High lipid content of the MV lesion and a contralateral location of lipid in the bifurcation area may contribute to SBOS after provisional stenting. © 2016 Wiley Periodicals, Inc.