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Balloon atrial septostomy (BAS) is an essential catheterization procedure for congenital heart lesions. Recently, a balloon catheter for static BAS was approved for the first time in Japan as an alternative to the conventional pull-through BAS. Despite the expected increase in the use of static BAS, reports on its safety are scarce worldwide.Methods and Results: Data on static and pull-through BAS registered in a national registry between 2016 and 2018 were collected. During the study period, 247 sessions of static BAS and 588 sessions of pull-through BAS were performed on a total of 674 patients. Patients who underwent static BAS were older (P0.001). The incidence of serious adverse events (4.3% vs. 0.9%, P=0.03) and the overall incidence of adverse events (8.1% vs. 3.2%, P=0.03) were higher in static BAS than in pull-through BAS. Among patients who underwent static BAS, the risk factor for adverse events was a body weight3 kg at the time of the procedure (odds ratio: 4.3 [confidence interval: 1.7-11], P=0.003).This nationwide study revealed differences in patient background between static and pull-through BAS, as well as a higher incidence of adverse events related to static BAS. Patients weighing3 kg are at high risk for adverse events after static BAS and may require surgical and circulatory support backup.

Background: In Japan, the choice of pediatric medical devices is limited because of 2 “device lag” problems: Japan lags behind the USA and Europe in device development, and development of pediatric devices lags behind that of adult devices. We aimed to identify the problems with and impediments to pediatric medical device development as recognized by pediatric physicians in Japan. Methods and Results: A voluntary survey of pediatric medical devices for all council members of the Japanese Society of Pediatric Cardiology and Cardiac Surgery was conducted in 2019. The response rate was 47.1% (154/327). The respondents were 115 pediatric cardiologists (74.7%) and 39 cardiovascular surgeons (25.3%). Approximately 90% believed that difficulties in development existed. Approximately 70% were dissatisfied with the pediatric medical devices currently available in Japan, which was a result of the unavailability of medical devices approved overseas, few types and sizes, and off-label use. Factors that hindered the development of pediatric medical devices included anatomical issues specific to children with congenital heart disease, as well as system issues such as lack of corporate profitability, development cost, and amount of time for development. Conclusions: Pediatric cardiologists and cardiovascular surgeons regard “device lag” and “off-label use” in Japan as important hindrances to the delivery of better medical care for pediatric patients with congenital heart disease.

Although a domestic trial in Japan revealed that Absorb bioresorbable vascular scaffold (BVS) has no inferiority to everolimus-eluting stent (EES) cohort in the primary endpoint of the target lesion failure at 12 months, the scaffold/stent thrombosis (ST) rates with the BVS at 24 months were higher than those with the EES (Absorb BVS 3.1% vs. EES 1.5%), the ST rate of 3.1% with Absorb BVS is not an acceptable level in Japan. A cause-of-ST analysis revealed that cases in which diagnostic imaging and ensuing post-dilatation had been performed appropriately had lower ST rates than those without such management (within 1 year: 1.37% vs. 7.69%, from 1 to 2 years: 0.00% vs. 8.33%). Therefore, a further evaluation was needed to confirm that the ST rate with the Absorb BVS would be reduced by a proper implementation procedure. Regulatory approval was given conditionally to initiate rigorous post-marketing data collection in order to ensure the proper use of this device in limited facilities. The One-year Use-Result Survey in Japan for the Absorb BVS revealed no instances of ST. This approach to reducing the premarket regulatory burden of clinical trials and enhancing the post-marketing commitments of medical device regulation is useful for expediting patient access to innovative medical devices.

In 2013, a drug-coated balloon catheter (DCB) (SeQuent Please) for the treatment of coronary in-stent restenosis (ISR) was approved in Japan. The pre-marketing Japan domestic NP001 study demonstrated better outcomes of the DCB (n = 138) compared to plain balloon angioplasty (n = 72). After the introduction to marketing, a post-marketing surveillance (PMS) (n = 396) was conducted to evaluate the safety and efficacy of the DCB in Japanese routine clinical practice. The aim of this paper was to assess differences between the pre-marketing NP001 study and the PMS. Compared to the NP001 study, more complex lesions were treated in the PMS (type B2/C: 69.0% vs 20.4%, total occlusion: 11.2% vs 0%, p

Background Stent thrombosis (ST) is a rare but serious complication after deployment of a drug-eluting stent. The features of ST after implantation of an everolimus-eluting stent (EES) have not been fully elucidated. Methods A comprehensive survey of real-world adverse event reporting with conditions for approval under the Pharmaceuticals and Medical Devices Act identified 490 cases of ST with EES. A total of 370 patients with definite ST after EES implantation [287 with early (E)ST (within 30 days), 54 with late (L)ST (31–365 days), and 29 with very late (VL)ST (over 1 year)] were divided into an EST group and an LST/VLST group to compare the patients and lesions characteristics. Results The frequency of patients with hemodialysis and in-stent restenosis (ISR) lesions were significantly higher in the LST/VLST group than in the EST group (hemodialysis, 22.9% vs 2.7%, p = 0.0001; ISR lesions, 25.9% vs 9.4%, p = 0.0001). Characteristic demographic factors for LST/VLST versus EST identified by multivariable model were hemodialysis and ISR lesions (hemodialysis: odds ratio 7.348, 95% confidence interval 2.458–21.968, p = 0.0001; ISR lesions: odds ratio, 2.490, 95% confidence interval 1.100–5.638, p = 0.027). The in-hospital death rates from ST were not significantly different between the EST group and the LST/VLST group (EST, 15% vs LST/VLST, 21.7%, p = 0.147). Conclusions Patient-related and lesion-related characteristics were significantly different between EST and LST/VLST. Data collection from adverse event reporting could be a helpful strategy for evaluation of this serious but rare complication.

In consultation with academia and the Pharmaceuticals and Medical Devices Agency (PMDA), we have developed guidance for drafting protocols for clinical trials concerning medical devices for the healing of hard-to-heal wounds without ischaemia. The guidance summarises the validity of single-arm trials for hard-to-heal wounds, the definition of hard-to-heal wounds without ischaemia, methods of patient enrolment and clinical endpoints. This review focuses on the logical thinking process that was used when establishing the guidance for improving the efficiency of clinical trials concerning medical devices for hard-to-heal wounds. We particularly focused on the feasibility of conducting single-arm trials and also tried to clarify the definition of hard-to-heal wounds. If the feasibility of randomised control trials is low, conducting single-arm trials should be considered for the benefit of patients. In addition, hard-to-heal wounds were defined as meeting the following two conditions: wounds with a wound area reduction

Regulatory approval processes for medical devices in Japan and the United States of America (US) often require similar clinical trials to establish safety and effectiveness. The Harmonization by Doing (HBD) program provides a collaborative environment for communication between regulators, academics and industry, facilitating the design and conduct of US/Japanese clinical trials supporting approval in both countries.

Background Stent thrombosis (ST) is a serious complication after drug-eluting stents (DES) implantation. To identify the risk factors of mortality following ST, we evaluated adverse event reports used for safety measures after approval.Methods and Results:Between July 2004 and August 2019, 2,887 ST case reports were submitted to the Pharmaceutical and Medical Device Agency. Reports of probable or possible ST (n=604), with insufficient data regarding in-hospital outcome or duration between procedure and ST occurrence (n=37) or duplicate reports (n=191) were excluded. Accordingly, 2,045 reports with definite ST were analyzed. Among the subjects, there were 286 in-hospital deaths (14.0%). Multivariate logistic regression analysis revealed that left main trunk (LMT) (odds ratio [OR]: 4.76, 95% confidence interval [CI]: 3.26-6.96), chronic heart failure (CHF) (OR: 2.88, 95% CI: 1.61-5.14), hemodialysis (OR: 2.69, 95% CI: 1.66-4.36), prior stroke (OR: 2.28, 95% CI: 1.15-4.51), over 70 years old (OR: 1.62, 95% CI: 1.22-2.16), and right coronary artery (OR: 0.41, 95% CI: 0.27-0.63) were independent factors for in-hospital death after DES-ST. Conclusions LMT, CHF, hemodialysis, prior stroke, and older age were independently associated with higher risk of in-hospital death following DES-ST. If target patients have these factors, maximum preventive strategies against ST occurrence, including adequate dual-antiplatelet therapy duration and optimal DES deployment procedures, are required.

Background The Harmonization By Doing (HBD) program was established in 2003 as a partnership among stakeholders of academia, industry and regulatory agencies in Japan and the United States, with a primary focus on streamlining processes of global medical device development for cardiovascular medical devices. While HBD has traditionally focused on development of devices intended to treat conditions prevalent in adults, in 2016, HBD established the "HBD-for-Children" program, which focuses on the development of pediatric devices as the development of medical devices for pediatric use lags behind that of medical devices for adults in both countries.Methods and Results:Activities of the program have included: (1) conducting a survey with industry to better understand the challenges that constrain the development of pediatric medical devices; (2) categorizing pediatric medical devices into five categories based on global availability and exploring concrete solutions for the early application and regulatory approval in both geographies; and (3) facilitating global clinical trials of pediatric medical devices in both countries. Conclusions The establishment of the HBD-for-Children program is significant because it represents a global initiative for the introduction of pediatric medical devices for patients in a timely manner. Through the program, academia, industry and regulatory agencies can work together to facilitate innovative pediatric device development from a multi-stakeholder perspective. This activity could also encourage industry partners to pursue the development of pediatric medical devices.

For more than 10 years, the Harmonization by Doing (HBD) program, a joint effort by members from academia, industry and regulators from the United States of America (USA) and Japan, has been working to increase timely regulatory approval for cardiovascular devices through the development of practical global clinical trial paradigms. Consistent with this mission and in recognition of the increasing global public health effects of critical limb ischemia (CLI), academic and government experts from the USA and Japan have developed a basic framework of global clinical trials for endovascular devices for CLI. Despite differences in medical and regulatory environments and complex patient populations in both countries, we developed a pathway for the effective design and conduct of global CLI device studies by utilizing common study design elements such as patients' characteristics and study endpoints, and minimizing the effect of important clinical differences. Some of the key recommendations for conducting global CLI device studies are: including patients on dialysis; using a composite primary endpoint for effectiveness that includes 6-month post-procedure therapeutic success and target vessel patency; and using a 30-day primary safety endpoint of perioperative death and major adverse limb events. The proposed approach will be uniquely beneficial in facilitating both the initiation and interpretation of CLI studies and accelerating worldwide CLI device development and innovation.

A prospective randomized clinical trial showed that the BioFreedom stent (Biosensors International), which is a polymer-free and carrier-free drug-coated stent, was significantly superior to a bare-metal stent (BMS) in patients at high bleeding risk who were receiving a 1-month course of dual antiplatelet therapy (DAPT). However, the stent thrombosis rate (2.01% for BioFreedom vs. 2.20% for BMS) was 4-6-fold higher than that of approved drug-eluting stents based on real-world data in Japan. Furthermore, the frequency of stent thrombosis at more than 1 month with the BioFreedom stent was slightly higher than that at less than 1 month. This result suggested that it would not be acceptable to stop DAPT universally at 1 month. Thus, the target patients for the BioFreedom stent are unspecified patients at high bleeding risk needing to continue DAPT for as long as necessary in Japan. Therefore, based on the pre- and post-marketing balance of medical devices regulations, regulatory approval was given for unspecified patients conditionally upon real-world data collection of 2,000 patients with a Use-Results Survey, instead of conducting additional pre-marketing clinical trial(s). The Use-Results Survey System is part of a strategy to expedite patients' access to innovative medical devices and to accelerate the development of medical devices.

The indication for MitraClip (Abbott Vascular, Santa Clara, CA, USA) in the USA is degenerative mitral regurgitation (DMR), but the Japanese indication includes both DMR and functional mitral regurgitation (FMR), in patients without severe left ventricular dysfunction. One of the reasons for this difference is that the Japanese Circulation Society submitted a formal request to the Japanese government for early approval of MitraClip for both DMR and FMR on the basis of unmet medical need for MR patients resistant to medical therapy, but at prohibitive risk for mitral valve surgery. Here, we describe the regulatory approval review process of MitraClip in Japan. Clinical data from outside Japan indicated that MitraClip provides significant improvements from baseline in New York Heart Association Class and hospitalizations for heart failure due to the reduction of MR grade without adversely affecting long-term prognosis in FMR patients as well as DMR patients. Also, a Japanese domestic trial showed a favorable acute procedural success rate without serious adverse events with MitraClip in both DMR and FMR patients. Further, it is considered in Japan that improvement of MR mechanically is clinically important in both DMR and FMR, in patients without severe left ventricular dysfunction. On the basis of these considerations, the MitraClip was approved in Japan for indications of both DMR and FMR with preserved cardiac function in patients at prohibitive risk for mitral valve surgery.

The lack of consistent definitions and nomenclature across clinical trials of novel devices, drugs, or biologics poses a significant barrier to accrual of knowledge in and across peripheral artery disease therapies and technologies. Recognizing this problem, the Peripheral Academic Research Consortium, together with the U.S. Food and Drug Administration and the Japanese Pharmaceuticals and Medical Devices Agency, has developed a series of pragmatic consensus definitions for patients being treated for peripheral artery disease affecting the lower extremities. These consensus definitions include the clinical presentation, anatomic depiction, interventional outcomes, surrogate imaging and physiological follow-up, and clinical outcomes of patients with lower-extremity peripheral artery disease. Consistent application of these definitions in clinical trials evaluating novel revascularization technologies should result in more efficient regulatory evaluation and best practice guidelines to inform clinical decisions in patients with lower extremity peripheral artery disease.

Objectives. After conventional balloon angioplasty (PTCA) for acute myocardial infarction in 77 patients (77 lesions), we used myocardial fractional flow reserve (FFR(myo)) to assess the endpoint of percutaneous coronary intervention (PCI) and to determine whether adjunctive stenting was required. Of these, a total of 37 lesions with FFRor = 0.94 after PTCA received no further treatment (FFR-PTCA group), while the remaining 40 lesions (FFR0.94) underwent adjunctive stenting (FFR-stent group). A further 78 patients (78 lesions) comprised the control group; these patients underwent direct stenting without FFR measurement (stent-only group). The restenosis rate at 14-day discharge (mean time to discharge) was 5.1% in the two groups treated with FFR guidance (FFR-PTCA and FFR-stent), but was 0% in the control group (p = ns). There were no significant differences in reocclusion rates between the FFR-guided patients (1.7%) and the controls (0%). There was no incidence of in-hospital mortality or reinfarction in any of the groups. The number of balloons used (mean, 1.3 0.6 balloons for FFR patients versus 1.8 0.5 balloons for control patients) and the total cost of hospitalization and treatment ($16,213 versus $19,730 in U.S. currency; 1,945,571 998,726 yen versus 2,367,656 538,444 yen in Japanese currency) were both higher in the control group. Long-term survival rates were comparable in the two groups. These findings indicate that FFR guidance for PCI of acute myocardial infarction is a useful, low-cost technique that results in similar clinical outcomes as primary stenting.

The aim of this study was to evaluate the effectiveness of cutting balloon angioplasty (CBA) in small vessels < 3.0 mm in diameter. Included were 166 patients (175 lesions) treated with CBA (CBA group), and 215 patients (240 lesions) were treated with plain old balloon angioplasty (POBA group). No differences were observed in patient backgrounds or lesion characteristics between the two groups. Procedural success rates were similar: 98.3% (CBA) versus 95.8% (POBA). Coronary dissection rates were also similar: 7.4% in the CBA versus 5.8% in the POBA group. Severe dissections (types E and F) occurred in 2.5% of cases in the POBA group, whereas there was none observed in the CBA group. In-hospital complications occurred in 3.3% in the POBA group, and in only 0.6% in the CBA group. The restenosis rate was 37.5% (CBA group) versus 48.1% (POBA group); and in vessels < 2.75 mm, restenosis was significantly lower in the CBA group than in the POBA group (36.9% vs 62.7%, P < 0.05). CBA may be a useful therapeutic strategy for small vessels, given the absence of severe coronary dissection and the significantly lower rate of restenosis compared to POBA.

A coronary flow reserve (CFR) of 2.0 has been advocated as the endpoint for coronary intervention therapy. Experience shows, however, that CFR does indeed exceed 2.0 in many cases poststenting, while remaining below 2.0 in others. In this study, we assessed the clinical characteristics and IVUS findings of patients whose CFR remained below 2.0 after stent implantation, specifically 16 patients with CFR below 2.0 (22 lesions, 64 ± 9 years, 4 female), and 102 patients with CFR above 2.0 (112 lesions, mean age 66 ± 11 years, 22 female). Patient population comprised patients selected for retrospective study, but participants were selected on the basis of matching patient and lesion characteristics. The IVUS findings showed that incidence of calcified lesions and post-PTCA dissection of hard plaque were higher among patients with CFR < 2.0. Further, IVUS-obtained vascular measurements showed post-PTCA area stenosis to be 58.7 ± 15.2% in the CFR < 2.0 group, and 45.3 ± 12.5% among CFR ≥ 2.0 patients (P < 0.05). These findings indicate that patients with diffuse calcified lesions or high post-PTCA % area stenosis, as determined by IVUS, are more likely to have lower CFR after stenting. Cathet Cardiovasc Intervent 2001;52:420–424. © 2001 Wiley-Liss, Inc.

First, we sincerely express our appreciation for the organized effort by the Valve Academic Research Consortium (VARC) members ([1][1]). Similar to the United States, there is no approved transcatheter aortic valve implantation (TAVI) device in Japan at present. We believe that this VARC consensus

Background Sarpogrelate, a serotonin blocker, has been reported to inhibit the serotonin-induced proliferation of rat aortic smooth muscle cells. The aim of this study was to investigate whether sarpogrelate reduces restenosis after coronary stenting as a result of prevention of intimal hyperplasia. Methods We examined 79 patients with stable angina undergoing elective coronary stenting on de novo lesions of native coronary arteries in a prospective, randomized trial. All enrolled patients received aspirin and ticlopidine, and one third of the patients were assigned to receive oral sarpogrelate. Results Treatment with sarpogrelate in addition to aspirin and ticlopidine caused no major adverse cardiovascular events or hemorrhagic adverse effects during the 6-month follow-up period. The restenosis rate in the group of patients receiving sarpogrelate was 4.3%, which was significantly lower than the 28.6% rate found in the group of patients not receiving sarpogrelate. Conclusions Sarpogrelate treatment reduces restenosis after coronary stenting, which suggests that serotonin released from activated platelets may play an important role in stent restenosis. (Am Heart J 2003:145:e16.)