Efficacy and Safety of Edoxaban in Anticoagulant Therapy Early After Surgical Bioprosthetic Valve Replacement: Rationale and Design of the ENBALV Trial.

BACKGROUND AND PURPOSE: Anticoagulant therapy with vitamin K antagonists is recommended within 3 to 6 months after bioprosthetic valve replacement to prevent thromboembolic events. However, data regarding whether direct oral anticoagulants can be an alternative to warfarin in such patients are limited. The purpose of this study is to compare the efficacy and safety of edoxaban versus warfarin within 3 months after bioprosthetic valve replacement. METHODS: The ENBALV trial is an investigator-initiated, phase 3, randomized, open-label, multicenter study. It involves patients aged 18 to 85 years undergoing bioprosthetic valve replacement at the aortic and/or mitral position. They are randomized 1:1 to receive either edoxaban or warfarin. Administration of edoxaban or warfarin is to be continued for 12 weeks after surgery. The primary outcome is the occurrence rate of stroke or systemic embolism at 12 weeks after surgery. The net clinical outcome is a composite of stroke, systemic embolism, or major bleeding, which is included in the secondary outcomes. CONCLUSION: The ENBALV trial demonstrates the efficacy and safety of edoxaban compared with warfarin in patients early after bioprosthetic valve replacement, including patients with sinus rhythm, which will bring a significant benefit to patients in clinical practice. TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCT) 2051210209. 30 Mar 2022 https://jrct.niph.go.jp/latest-detail/jRCT2051210209 .

A Novel Extracorporeal Continuous-Flow Ventricular Assist System for Patients With Advanced Heart Failure　- Initial Clinical Experience.

BACKGROUND: Bridge-to-decision (BTD) devices providing temporary mechanical circulatory support should be introduced to patients with advanced heart failure. This study evaluated the effectiveness and safety of a BTD device comprising an innovative extracorporeal continuous-flow temporary ventricular assist device (VAD) driven by a novel hydrodynamically levitated centrifugal flow blood pump.Methods and Results:Nine patients, comprising 3 with dilated cardiomyopathy, 3 with fulminant myocarditis, and 3 with ischemic heart disease, and 6 males, whose mean age was 47.7±8.1 years, were enrolled into the study. Six patients had Interagency Registry for Mechanically Assisted Circulatory Support profile 1, and 3 were profile 2. The primary endpoint was a composite of survival free from device-related serious adverse events and complications during circulatory support. Eight patients received left ventricular support, of whom 3 received concomitant right ventricular support using extracorporeal membrane oxygenation circuits, as a consequence of severe respiratory failure. One patient with fulminant myocarditis received biventricular support using the novel VAD system. After 19.0±13.5 days, 3 patients were weaned from circulatory support, because their native cardiac function recovered, and 6 patients required conversion to a durable device as a bridge-to-transplantation. One patient had non-disabling ischemic stroke episodes, and no patients died. CONCLUSIONS: This novel extracorporeal VAD system with a hydrodynamically levitated centrifugal pump can safely and successfully bridge patients with advanced heart failure to subsequent therapeutic stages.

"BAX602" in Preventing Surgical Adhesion after Extracorporeal Ventricular Assist Device Implantation for Refractory Congestive Heart Failure: Study Protocol for a Multicenter Randomized Clinical Trial.

BACKGROUND: The high surgical risk in redo cardiac surgery is largely attributed to adhesions around the epicardium and the great vessels. BAX602 is an adhesion prevention reagent composed of two synthetic polyethylene glycols. Spraying BAX602 over the epicardium and the great vessels reportedly contributes to adhesion prevention after pediatric cardiac surgery. The present study aims to evaluate the safety and effectiveness of BAX602 spray in patients undergoing extracorporeal ventricular assist device implantation surgery to treat refractory congestive heart failure. METHODS AND DESIGN: This investigator-initiated, multicenter, pivotal, two-arm, open-label, randomized trial will include a total of 30 patients. The primary outcome measure is the severity of adhesions, which will be evaluated during re-sternotomy surgery performed 2-12 weeks after the primary extracorporeal ventricular assist device implantation surgery. The adhesion severity will be evaluated at five predefined sites using a four-grade adhesion evaluation score (0 = no adhesion; 1 = filmy and avascular adhesion; 2 = dense/vascular adhesion; 3 = cohesive adhesion). This measure will be summarized in two ways to evaluate the effect of BAX602: (1) the total score of the severity of adhesions at all five sites (ranging from 0 to 15), and (2) the total number of sites with dense/vascular or cohesive adhesions (ranging from 0 to 5). ETHICS AND DISSEMINATION: The study findings will be disseminated at regional, national, and international conferences and through peer-reviewed scientific journals. TRIAL REGISTRATION: The trial was registered in the UMIN Clinical Trials Registry (UMIN-CTR: UMIN000038998) on 6 January 2020.

Assessment of Safety and Effectiveness of the Extracorporeal Continuous-Flow Ventricular Assist Device (BR16010) Use as a Bridge-to-Decision Therapy for Severe Heart Failure or Refractory Cardiogenic Shock: Study Protocol for Single-Arm Non-randomized, Uncontrolled, and Investigator-Initiated Clinical Trial.

BACKGROUND: The management of heart failure patients presenting in a moribund state remains challenging, despite significant advances in the field of ventricular assist systems. Bridge to decision involves using temporary devices to stabilize the hemodynamic state of such patients while further assessment is performed and a decision can be made regarding patient management. The purpose of this study (NCVC-BTD_01, National Cerebral and Cardiovascular Center-Bridge to Dicision_01) is to assess the safety and effectiveness of the newly developed extracorporeal continuous-flow ventricular assist system employing a disposable centrifugal pump with a hydrodynamically levitated bearing (BR16010) use as a bridge-to-decision therapy for patients with severe heart failure or refractory cardiogenic shock. METHOD/DESIGN: NCVC-BTD_01 is a single-center, single-arm, open-label, exploratory, medical device, investigator-initiated clinical study. It is conducted at the National Cerebral and Cardiovascular Center in Japan. A total of nine patients will be enrolled in the study. The study was planned using Simon's minimax two-stage phase design. The primary endpoint is a composite of survival free of device-related serious adverse events and complications during device support. For left ventricular assistance, withdrawal of a trial device due to cardiac function recovery or exchange to other ventricular assist devices (VADs) for the purpose of bridge to transplantation (BTT) during 30 days after implantation will be considered study successes. For right ventricular assistance, withdrawal of tal device due to right ventricular function recovery within 30 days after implantation will be considered a study success. Secondary objectives include changes in brain natriuretic peptide levels (7 days after implantation of a trial device and the day of withdrawal of a trial device), period of mechanical ventricular support, changes in left ventricular ejection fraction (7 days after implantation of a trial device and the day of withdrawal of a trial device), and changes in left ventricular diastolic dimension (7 days after implantation of a trial device and the day of withdrawal of a trial device). ETHICS AND DISSEMINATION: We will disseminate the findings through regional, national, and international conferences and through peer-reviewed journals. TRIAL REGISTRATION: UMIN Clinical Trials Registry (UMIN-CTR; R000033243) registered on 8 September 2017.

Rationale and Design of a Prospective, Multicenter, Single-Arm Clinical Trial to Investigate the Safety and Effectiveness of Rotablator Atherectomy System as an Adjunctive Device for Endovascular Treatment of Occlusive Atherosclerotic Lesions in Below-the-Knee Arteries With Critical Limb Ischemia (RESCUE-BTK).

Background: Endovascular treatment with balloon angioplasty plays a major role in revascularization of below-the-knee (BTK) arteries in patients with critical limb ischemia (CLI). However, with severely calcified lesions, achieving optimal revascularization with balloon angioplasty alone is difficult. Therefore, we are evaluating the safety and effectiveness of the Rotablator atherectomy system as an adjunctive device in the treatment of severely calcified lesions in BTK arteries in the RESCUE-BTK trial, a multicenter, single-arm, open-label, exploratory investigator-initiated clinical study of medical devices. In this paper we describe the design of the trial. Methods and Results: Seventeen patients with CLI in whom balloon angioplasty has failed are enrolled in the study. The primary endpoint is the procedural success rate of balloon angioplasty after rotational atherectomy. Success is defined as the fulfillment of 3 requirements upon assessment by the core laboratory: (1) final residual diameter stenosis <50%; (2) the absence of a delay in flow or vessel perforation in the target artery, or both; and (3) brisk antegrade flow to the foot. Key secondary endpoints are the number of complications associated with the trial procedures and the limb salvage rate. Participants are followed-up for 6 months after the trial procedures. Conclusions: The RESCUE-BTK trial will clarify the safety and effectiveness of the adjunctive use of the Rotablator system in severely calcified lesions of BTK arteries in patients with CLI.

Landiolol, an ultra-short acting beta-1 blocker, for preventing postoperative lung cancer recurrence: study protocol for a phase III, multicenter randomized trial with two parallel groups of patients.

BACKGROUND: Recurrence of cancer after curative surgery is a major problem after most cancer treatments. Increased sympathetic activity during the perioperative period could promote cancer cell invasion to blood vessels and angiogenesis, resulting in cancer metastasis. Recent studies showed that use of beta blockers can be associated with the prolonged survival of patients with cancer. The objective of this study is to evaluate the preventive effects of landiolol hydrochloride, which is an ultra-short-acting beta-1-selective blocker that has been developed in Japan, on reducing recurrence of cancer after curative surgery for patients with lung cancer. METHODS: The present study is a phase III, multicenter, randomized trial with two parallel groups of patients with lung cancer, comparing surgery alone and surgery with landiolol administration for three days during the perioperative period. A total of 400 patients will be enrolled from 12 Japanese institutions. The primary endpoint is two-year relapse-free survival and overall survival after curative surgery for lung cancer. The secondary endpoints are additional treatment after recurrence of cancer, safety events, and the incidence of postoperative complications. DISCUSSION: The principal question addressed in this trial is whether landiolol can reduce recurrence of cancer after curative surgery for lung cancer. TRIAL REGISTRATION: Japan Registry of Clinical Trials, jRCT2011180004. Registered 17 January 2019.

Evaluating the safety and technical effectiveness of a newly developed intravascular 'flow isolator' stent for the treatment of intracranial aneurysms: study protocol for a first-in-human single-arm multiple-site clinical trial in Japan.

INTRODUCTION: Wide-neck or large intracranial aneurysms are difficult to cure by conventional surgical or endovascular procedures. A flow diverter (FD) is an implantable, stent-like, fine-mesh medical device for the treatment of intracranial aneurysms. Although endovascular treatment with FDs is becoming a routine first-line option, a systematic review noted the heterogeneity and publication biases of the clinical studies for FDs. We have developed a new honeycomb microporous covered stent (NCVC-CS1) as a 'flow isolator' for the endovascular treatment of intracranial aneurysms. METHODS AND ANALYSIS: We planned the NCVC-CS1_UAN as a first-in-human study to evaluate the safety and technical effectiveness of the NCVC-CS1, a newly developed honeycomb microporous covered stent, for the treatment of intracranial aneurysms that are difficult to cure by conventional surgical or endovascular procedures. The study is a multicentre, open-label, uncontrolled, exploratory, medical device, investigator-initiated clinical study. The primary safety endpoint of this study is any stroke or death related to the procedure within 180 days, while for efficacy, the endpoint is complete obliteration of the target aneurysm and patency of the target vessel (less than 50% stenosis) confirmed by angiography at 180 days after the procedure. ETHICS AND DISSEMINATION: Full ethics approval of institutional review boards was obtained at all participating sites. A clinical trial notification as a new medical device was accepted by the Japanese regulatory agency before it started. The study should be followed by a pivotal study to obtain satisfactory data for an application for marketing approval. The main results of this study will be submitted for publication in a peer-reviewed journal. The planned subject number for this study is 12. TRIAL REGISTRATION NUMBER: NCT02907229.

A multicenter randomized controlled trial of surgery alone or surgery with atrial natriuretic peptide in lung cancer surgery: study protocol for a randomized controlled trial.

BACKGROUND: Postoperative cancer recurrence is a major problem following curative surgery. In a previous retrospective study of lung cancer surgery, we reported that administration of atrial natriuretic peptide (ANP) during the perioperative period reduced postoperative recurrence. We demonstrated that ANP inhibited the adhesion of cancer cells to vascular endothelium as a vasoprotective action. The objective of this study is to evaluate the effects of ANP on the incidence of postoperative cancer recurrence in lung cancer surgery. METHODS/DESIGN: The present study is a multicenter, randomized trial with two parallel groups of patients with lung cancer comparing surgery alone and surgery with ANP administration for 3 days during the perioperative period. A total of 500 patients will be enrolled from 10 Japanese institutions. The primary endpoint is 2-year relapse-free survival (RFS). The secondary endpoints are 2-year cancer-specific RFS, 5-year RFS, overall survival, the incidence of postoperative complications, and the completion rate of ANP treatment. DISCUSSION: The principal question addressed in this trial is whether ANP with its vasoprotective action can reduce cancer recurrence following lung cancer surgery. TRIAL REGISTRATION: UMIN Clinical Trials Registry identifier: UMIN000018480 . Registered on 31 July 2015.