A Pharmacokinetic/Pharmacodynamic Study of Esomeprazole Comparing a Dual Delayed-Release Formulation (YYD601) to a Conventional Formulation Following Multiple Administrations in Healthy Adult Subjects

Hae Won Lee,1 Woo Youl Kang,2 Ji Seo Park,1 Jae Hwa Lee,1 Jin Ju Park,1 Mi-Ri Gwon,1 Young-Ran Yoon,1 Sook Jin Seong1 1School of Medicine, Kyungpook National University and Department of Clinical Pharmacology and Therapeutics, Kyungpook National University Hospital, Daegu, 41944, Republic of Korea; 2Clinical Trial Dossier Evaluation Team, Innovative Products Support Department, National Institute of Food and Drug Safety Evaluation, Cheongju, 28159, Republic of KoreaCorrespondence: Young-Ran Yoon, Professor, School of Medicine, Kyungpook National University and Department of Clinical Pharmacology and Therapeutics, Kyungpook National University Hospital, 130 Dongdeok-Ro, Jung-gu, Daegu, 41944, Republic of Korea, Tel +82-53-420-4950, +82-53-420-5218, Email [email protected] Sook Jin Seong, Clinical Associate Professor, School of Medicine, Kyungpook National University and Department of Clinical Pharmacology and Therapeutics, Kyungpook National University Hospital, 130 Dongduk-Ro, Jung-gu, Daegu, 41944, Republic of Korea, Tel +82-53-200-6351, +82-53-420-5218, Email [email protected]: YYD601 is a new dual delayed-release formulation of esomeprazole, developed to enhance plasma exposure and prolong the duration of acid suppression.Purpose: This study aimed to evaluate the safety, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of YYD601 20 mg following single and multiple oral administrations in healthy, fasting adult Koreans, and to compare these outcomes to those of the conventional esomeprazole 20 mg capsule.Methods: A randomized, open-label, two-period crossover study was conducted in 28 participants, who were divided into two treatment groups: one group received YYD601 20 mg, and the other received conventional esomeprazole 20 mg, once daily for five consecutive days. Blood samples for PK analysis were collected pre-dose and up to 24 hours post-dose. The primary PK parameters (AUClast and AUCτ) were evaluated. PD endpoints included integrated gastric acidity, percentage of time with intragastric pH > 4 over 24-hour and nighttime intervals, and percent change in serum gastrin levels after multiple dosing.Results: A total of 22 participants completed the study. YYD601 displayed more prolonged plasma concentration-time profiles than the conventional formulation, although the extent of the systemic exposure (AUC values) showed no statistically significant difference between the two formulations. With regard to the 24-hour gastric acid inhibition, YYD601 was comparable to the conventional formulation. The YYD601 showed a greater tendency for acid inhibition at night, as indicated by the percentage change of time with nocturnal acid breakthrough and other PD parameters. Both treatments were well tolerated, with no serious adverse events reported.Conclusion: Through extended systemic exposure of esomeprazole, YYD601 produces gastric acid suppression that is comparable to that of the conventional esomeprazole formulation, with a greater tendency to suppress acid at night. YYD601 20 mg was safe and well tolerated following single and multiple oral administrations, supporting its use as an effective alternative to conventional esomeprazole therapy.Clinical Trial Registry: http://clinicaltrials.gov, NCT03985319 (Date of registration: May 29, 2019; Study period: between July 2019 and March 2020).Keywords: esomeprazole, dual delayed-release formulation, pharmacokinetics, pharmacodynamic

Occupational radiation exposure in femoral artery approach is higher than radial artery approach during coronary angiography or percutaneous coronary intervention

Medical radiation exposure is a significant concern for interventional cardiologists (IC). This study was aimed at estimating the radiation exposure of IC operators and assistants in real clinical practice. The radiation exposure of the operator and assistant was evaluated by conducting two types of procedures via coronary angiography (CAG) and percutaneous coronary intervention (PCI) on 1090 patients in 11-cardiovascular centers in Korea. Radiation exposure was measured using an electronic personal dosimeter (EPD). EPD were attached at 3 points on each participant: on the apron on the left anterior chest (A1), under the apron on the sternum (A2), and on the thyroid shield (T). Average radiation exposure (ARE) of operators at A1, A2, and T was 19.219 uSv, 4.398 uSv, and 16.949 uSv during CAG and 68.618 uSv, 15.213 uSv, and 51.197 uSv during PCI, respectively. ARE of assistants at A1, A2, and T was 4.941 uSv, 0.860 uSv, and 5.232 uSv during CAG and 20.517 uSv, 4.455 uSv, and 16.109 uSv during PCI, respectively. AED of operator was 3.4 times greater during PCI than during CAG

Differential prognostic impact of treatment strategy among patients with left main versus non-left main bifurcation lesions undergoing percutaneous coronary intervention: results from the COBIS (Coronary Bifurcation Stenting) Registry II.

OBJECTIVES: The authors sought to investigate whether the impact of treatment strategies on clinical outcomes differed between patients with left main (LM) bifurcation lesions and those with non-LM bifurcation lesions. BACKGROUND: Few studies have considered anatomic location when comparing 1- and 2-stent strategies for bifurcation lesions. METHODS: We compared the prognostic impact of treatment strategies on clinical outcomes in 2,044 patients with non-LM bifurcation lesions and 853 with LM bifurcation lesions. The primary outcome was target lesion failure (TLF) defined as a composite of cardiac death, myocardial infarction (MI), and target lesion revascularization. RESULTS: The 2-stent strategy was used more frequently in the LM bifurcation group than in the non-LM bifurcation group (40.3% vs. 20.8%, p < 0.01). During a median follow-up of 36 months, the 2-stent strategy was not associated with a higher incidence of cardiac death (hazard ratio [HR]: 1.24; 95% confidence interval [CI]: 0.72 to 2.14; p = 0.44), cardiac death or MI (HR: 1.12; 95% CI: 0.58 to 2.19; p = 0.73), or TLF (HR: 1.39; 95% CI: 0.99 to 1.94; p = 0.06) in the non-LM bifurcation group. In contrast, in patients with LM bifurcation lesions, the 2-stent strategy was associated with a higher incidence of cardiac death (HR: 2.43; 95% CI: 1.05 to 5.59; p = 0.04), cardiac death or MI (HR: 2.09; 95% CI: 1.08 to 4.04; p = 0.03), as well as TLF (HR: 2.38; 95% CI: 1.60 to 3.55; p < 0.01). Significant interactions were present between treatment strategies and bifurcation lesion locations for TLF (p = 0.01). CONCLUSIONS: The 1-stent strategy, if possible, should initially be considered the preferred approach for the treatment of coronary bifurcation lesions, especially LM bifurcation lesions. (Korean Coronary Bifurcation Stenting [COBIS] Registry II; NCT01642992)

5-Year Outcome of Simple Crossover Stenting in Coronary Bifurcation Lesions Compared With Side Branch Opening

Background: The optimal side branch (SB) treatment strategy after simple crossover stenting in bifurcation lesions is still controversial. Objectives: The purpose of this study was to compare the long-term outcomes of a 1-stent strategy with simple crossover alone versus with an additional SB–opening procedure in patients with left main (LM) and non-LM coronary bifurcation lesions. Methods: Patients who underwent percutaneous coronary intervention with a 1-stent strategy for bifurcation lesions including LM were selected from the COBIS (Coronary Bifurcation Stenting) III registry and divided into the simple crossover–alone group and SB-opening group. Clinical outcomes were assessed by the 5-year rate of target lesion failure (a composite of cardiac death, target vessel myocardial infarction, and target lesion repeat revascularization). Results: Among 2,194 patients who underwent the 1-stent strategy, 1,685 (76.8%) patients were treated with simple crossover alone, and 509 (23.2%) patients were treated with an additional SB-opening procedure. Although the baseline SB angiographic disease was more severe in the SB-opening group, the final lumen diameter of the SB was larger. The 5-year observed target lesion failure rate was similar between the 2 groups (7.0% in the simple crossover vs. 6.7% in SB-opening group; hazard ratio: 0.99; 95% confidence interval: 0.66 to 1.48; p = 0.947), even in the subgroup analyses including LM (9.5% vs. 11.3%; p = 0.442) and true bifurcation (5.3% vs. 7.8%; p = 0.362). The results were not changed after an inverse probability of treatment weighting adjustment. There was no difference in the overall and SB-related target lesion revascularization rate in both groups. Conclusions: The long-term clinical outcome of the 1-stent strategy with simple crossover alone for coronary bifurcation lesions was acceptable compared to those of additional SB-opening procedures. (Korean Coronary Bifurcation Stenting [COBIS] Registry III [COBIS III]; NCT03068494

Transradial Versus Transfemoral Access for Bifurcation Percutaneous Coronary Intervention Using Second-Generation Drug-Eluting Stent

BACKGROUND: The benefits of transradial access (TRA) over transfemoral access (TFA) for bifurcation percutaneous coronary intervention (PCI) are uncertain because of the limited availability of device selection. This study aimed to compare the procedural differences and the in-hospital and long-term outcomes of TRA and TFA for bifurcation PCI using second-generation drug-eluting stents (DESs). METHODS: Based on data from the Coronary Bifurcation Stenting Registry III, a retrospective registry of 2,648 patients undergoing bifurcation PCI with second-generation DES from 21 centers in South Korea, patients were categorized into the TRA group (n = 1,507) or the TFA group (n = 1,141). After propensity score matching (PSM), procedural differences, in-hospital outcomes, and device-oriented composite outcomes (DOCOs; a composite of cardiac death, target vessel-related myocardial infarction, and target lesion revascularization) were compared between the two groups (772 matched patients each group). RESULTS: Despite well-balanced baseline clinical and lesion characteristics after PSM, the use of the two-stent strategy (14.2% vs. 23.7%, P = 0.001) and the incidence of in-hospital adverse outcomes, primarily driven by access site complications (2.2% vs. 4.4%, P = 0.015), were significantly lower in the TRA group than in the TFA group. At the 5-year follow-up, the incidence of DOCOs was similar between the groups (6.3% vs. 7.1%, P = 0.639). CONCLUSION: The findings suggested that TRA may be safer than TFA for bifurcation PCI using second-generation DESs. Despite differences in treatment strategy, TRA was associated with similar long-term clinical outcomes as those of TFA. Therefore, TRA might be the preferred access for bifurcation PCI using second-generation DES. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03068494

Bifurcation strategies using second-generation drug-eluting stents on clinical outcomes in diabetic patients

BACKGROUND: Diabetes mellitus (DM) is a critical risk factor for the pathogenesis and progression of coronary artery disease, with a higher prevalence of complex coronary artery disease, including bifurcation lesions. This study aimed to elucidate the optimal stenting strategy for coronary bifurcation lesions in patients with DM. METHODS: A total of 905 patients with DM and bifurcation lesions treated with second-generation drug-eluting stents (DES) from a multicenter retrospective patient cohort were analyzed. The primary outcome was the 5-year incidence of target lesion failure (TLF), which was defined as a composite of cardiac death, target vessel myocardial infarction, and target lesion revascularization. RESULTS: Among all patients with DM with significant bifurcation lesions, 729 (80.6%) and 176 (19.4%) were treated with one- and two-stent strategies, respectively. TLF incidence differed according to the stenting strategy during the mean follow-up of 42 +/- 20 months. Among the stent strategies, T- and V-stents were associated with a higher TLF incidence than one-stent strategy (24.0 vs. 7.3%, p &lt; 0.001), whereas no difference was observed in TLF between the one-stent strategy and crush or culotte technique (7.3 vs. 5.9%, p = 0.645). The T- or V-stent technique was an independent predictor of TLF in multivariate analysis (hazard ratio, 3.592; 95% confidence interval, 2.117-6.095; p &lt; 0.001). Chronic kidney disease, reduced left ventricular ejection fraction, and left main bifurcation were independent predictors of TLF in patients with DM. CONCLUSION: T- or V-stenting in patients with DM resulted in increased cardiovascular events after second-generation DES implantation. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT03068494?term=03068494&draw=2&rank=1, identifier: NCT03068494

Differential factors for predicting outcomes in left main versus non-left main coronary bifurcation stenting

Background: No large-scale study has compared the clinical and angiographic predictors of cardiovascular events in patients with left main bifurcation (LMB) and non-LMB stenting after second-generation DES implantation. Herein, we investigated differential clinical and angiographic factors for predicting outcomes in LMB versus non-LMB stenting. Methods: A total of 2648 patients with bifurcation lesions treated with second-generation DESs from the retrospective patient cohort were divided into an LMB group (n = 935) and a non-LMB group (n = 1713). The primary outcome was the 7-year incidence of target lesion failure (TLF), defined as the composite of cardiac death, myocardial infarction, and target lesion revascularization. Results: The incidence of TLF was 9.8%. Those in the LMB group were associated with a higher risk of TLF (14.2% versus 7.5%, p &lt; 0.001) than those in the non-LMB group. Regarding the LMB group, independent predictors of TLF were chronic kidney disease (CKD), reduced left ventricular ejection fraction (LVEF), and two-stenting. Regarding the non-LMB group, CKD, reduced LVEF, old age, diabetes, and small diameter of the main vessel stent were independent predictors of TLF. Conclusions: The two-stent strategy could potentially increase TLF for the LMB lesions, and achieving the maximal diameter of the main vessel stent could result in better clinical outcomes for non-LMB lesions

Differential Long-Term Effects of First- and Second-Generation DES in Patients With Bifurcation Lesions Undergoing PCI

Background: There is a paucity of data regarding the long-term clinical outcomes of first- versus second-generation drug-eluting stent (DES), especially when used to treat complex lesions such as bifurcation lesions. Objectives: The current study compares the efficacy and safety of first- versus second-generation DES at the 5-year follow-up in patients who underwent bifurcation percutaneous coronary intervention (PCI). Methods: A total of 5,498 patients with a bifurcation lesion who underwent PCI were pooled at a single patient level from COBIS (Coronary Bifurcation Stenting) registries II and III. Five-year target lesion failure (TLF) (the composite of cardiac death, myocardial infarction [MI], and target lesion revascularization [TLR]) and cardiac death or MI were compared between the use of first-generation DES (n = 2,436) and second-generation DES (n = 3,062) during PCI. Propensity score matching was performed to reduce selection bias. Results: After a 1:1 propensity score matching procedure was conducted, the cohort consisted of 1,702 matched pairs. Patients treated with second-generation DES had a significantly lower risk of TLF at 5 years than those treated with first-generation DES in both overall and propensity-matched populations (matched hazard ratio [HRmatched]: 0.576; 95% confidence interval [CI]: 0.456 to 0.727; p &lt;0.001). There were no significant differences in risk of a composite of cardiac death or MI between the 2 groups (HRmatched: 0.782; 95% CI: 0.539 to 1.133, P = 0.193). However, among patients who required a 2-stent technique, use of the second-generation DES reduced cardiac death or MI (HRmatched:0.422; 95% CI: 0.209 to 0.851, P = 0.016). On the other hand, among patients who required a one-stent technique, the risk of a composite of cardiac death or MI was similar between the 2 groups (HRmatched: 1.046; 95% CI: 0.664 to 1.650, P = 0.845). There was a significant interaction between stent generation and treatment strategy for cardiac death or MI (interaction P = 0.029). Conclusions: In patients treated with PCI for a bifurcation lesion, the use of second-generation DES was associated with a significantly reduced risk of 5-year TLF than the use of first-generation DES. (Korean Coronary Bifurcation Stenting Registry II [NCT01642992]; COBIS II) (Korean Coronary Bifurcation Stenting Registry III [NCT03068494] COBIS III

Ten-year trends in coronary bifurcation percutaneous coronary intervention: Prognostic effects of patient and lesion characteristics, devices, and techniques

BACKGROUND: Despite advances in devices and techniques, coronary bifurcation lesion remains a challenging lesion subset in the field of percutaneous coronary intervention (PCI). We evaluate 10-year trends in bifurcation PCI and their effects on patient outcomes. METHODS AND RESULTS: We analyzed 10-year trends in patient/lesion characteristics, devices, PCI strategy, stent optimization techniques, and clinical outcomes using data from 5498 patients who underwent bifurcation PCI from 2004 to 2015. Clinical outcomes 2 years after the index procedure were evaluated in terms of target vessel failure (a composite of cardiac death, myocardial infarction, and target vessel revascularization) and a patient-oriented composite outcome (a composite of all-cause death, myocardial infarction, and any revascularization). During the 10-year study period, patient and lesion complexity, such as multivessel disease, diabetes mellitus, chronic kidney disease, and left main bifurcation, increased continuously (all P&lt;0.001). The risk of target vessel failure or patient-oriented composite outcome decreased continuously from 2004 to 2015 (target vessel failure: from 12.3% to 6.9%, log-rank P&lt;0.001; patient-oriented composite outcome: from 13.6% to 9.3%, log-rank P&lt;0.001). The use of a second-generation drug-eluting stent and decreased target vessel failure risk in true bifurcation lesions were the major contributors to improved patient prognosis (interaction P values were &lt;0.001 and 0.013, respectively). CONCLUSIONS: During the past decade of bifurcation PCI, patient and lesion characteristics, devices, PCI techniques, and patient prognosis have all significantly changed. Despite increased patient and lesion complexity, clinical outcomes after bifurcation PCI have improved, mainly because of better devices and more widespread adoption of procedural optimization techniques and appropriate treatment strategies. REGISTRATION: URL: https://www.clini​caltr​ials.gov; Unique identifiers: NCT01642992 and NCT03068494

Scintillation light detection in the 6-m drift-length ProtoDUNE Dual Phase liquid argon TPC

DUNE is a dual-site experiment for long-baseline neutrino oscillation studies, neutrino astrophysics and nucleon decay searches. ProtoDUNE Dual Phase (DP) is a 6  ×  6  ×  6 m 3 liquid argon time-projection-chamber (LArTPC) that recorded cosmic-muon data at the CERN Neutrino Platform in 2019-2020 as a prototype of the DUNE Far Detector. Charged particles propagating through the LArTPC produce ionization and scintillation light. The scintillation light signal in these detectors can provide the trigger for non-beam events. In addition, it adds precise timing capabilities and improves the calorimetry measurements. In ProtoDUNE-DP, scintillation and electroluminescence light produced by cosmic muons in the LArTPC is collected by photomultiplier tubes placed up to 7 m away from the ionizing track. In this paper, the ProtoDUNE-DP photon detection system performance is evaluated with a particular focus on the different wavelength shifters, such as PEN and TPB, and the use of Xe-doped LAr, considering its future use in giant LArTPCs. The scintillation light production and propagation processes are analyzed and a comparison of simulation to data is performed, improving understanding of the liquid argon properties