Procedural Feasibility and Peri-procedural Outcomes of Peripheral Endovascular Therapy via Transradial versus Transfemoral Access: A Systematic Review and Meta-Analysis.

OBJECTIVE: This systematic review and meta-analysis aimed to evaluate the safety and feasibility of transradial access for peripheral vascular interventions. DATA SOURCES: MEDLINE and Embase. REVIEW METHODS: MEDLINE and Embase databases were searched to June 2023 to identify studies investigating the outcomes of peripheral vascular interventions in lower extremity, carotid, and visceral arteries via transradial vs. transfemoral access. The primary outcome was procedural failure rate. Secondary outcomes were total access site complications, minor and major bleeding, stroke, access vessel occlusion, procedural time, fluoroscopy time, and contrast volume. RESULTS: Eight randomised controlled trials and 29 observational studies yielded a total of 70 882 patients treated via transradial (n = 2 616) vs. transfemoral access (n = 68 338). The overall failure rate was 2.3 ± 0.7%, and the transradial approach was associated with a statistically significantly higher procedural failure rate than the transfemoral approach (3.9 ± 0.7% vs. 1.0 ± 0.3%; odds ratio [OR] 3.07, 95% confidence interval [CI] 1.84 - 5.12; I2 = 32%; p < .001). Subgroup analysis showed the highest failure rate in lower extremity interventions with 12.4 ± 4.9% for transradial vs. 4.0 ± 1.2% for transfemoral access. Conversely, procedural complications were statistically significantly fewer with transradial access for total access site complications (OR 0.64, 95% CI 0.45 - 0.91; I2 = 36%; p = .010). Minor bleeding was statistically significantly less with the transradial approach (OR 0.52, 95% CI 0.31 - 0.86; I2 = 30%; p = .010), whereas major bleeding and stroke rates were similar. Transradial access had more access vessel occlusion than transfemoral access (1.9% ± 0.5% vs. < 0.1% ± 0.0%; p = .004), although most remained asymptomatic. Procedural time, fluoroscopy time, and contrast volume were all comparable. GRADE certainty was low to moderate in most outcomes. CONCLUSION: The transradial approach was associated with a higher procedural failure rate. Total access site complications and minor bleeding were lower with the transradial approach, albeit with more frequent access vessel occlusion. Transradial access may be a feasible and safe approach; however, appropriate patient selection is imperative.

Clinical efficacy of tolvaptan in acute decompensated heart failure patients with severe aortic stenosis and atrial fibrillation: a sub-analysis from the LOHAS registry.

BACKGROUND: Severe aortic valve stenosis (AS) and atrial fibrillation (AF) are risk factors of hemodynamic instability in heart failure (HF) management due to low cardiac output, respectively. Therefore, the treatment of HF due to severe AS complicated with AF is anticipated to be difficult. Tolvaptan, a vasopressin V2 receptor inhibitor, is effective in controlling acute decompensated heart failure (ADHF) with hemodynamic stability. However, its clinical efficacy against ADHF caused by AS with AF remains to be determined. METHODS: Clinical information (from September 2014 to December 2017) of 59 patients diagnosed with ADHF due to severe AS (20 patients with AF; 39 patients with sinus rhythm [SR]) was obtained from the LOHAS registry. The registry collected data from seven hospitals and assessed the short-term effects of tolvaptan in patients hospitalized for ADHF with severe AS. We attempted to identify clinical differences from baseline up to 4 days, comparing patients with AF (AF group) versus those with SR (SR group). RESULTS: There were no significant differences between the groups in age (83.7 ± 4.5 vs. 85.8 ± 6.9 years, respectively; p = 0.11) and aortic valve area (0.60 [0.46-0.73] vs. 0.56 [0.37-0.70] cm2, respectively; p = 0.50). However, left atrial volume was larger (104 [85-126] vs. 87 [64-103] mL, respectively; p < 0.01), whereas stroke volume was lower (51.6 ± 14.8 vs. 59.0 ± 18.7 mL, respectively; p = 0.08) in the AF group versus the SR group. Body weight decreased daily from baseline up to day 4 in both groups (from 55.4 to 53.2 kg [p < 0.01] and from 53.5 to 51.0 kg [p < 0.01], respectively) without change in heart rate. Notably, the systolic blood pressure decreased slightly in the AF group after 2 days of treatment with tolvaptan. CONCLUSIONS: Short-term treatment with tolvaptan improved HF in patients hospitalized for severe AS, regardless of the presence of AF or SR. After achieving sufficient diuresis, a slight decrease in blood pressure was observed in the AF group, suggesting an appropriate timeframe for safe and effective use of tolvaptan.

Frailty, Sarcopenia, Cachexia, and Malnutrition in Heart Failure.

With global aging, the number of patients with heart failure has increased markedly. Heart failure is a complex condition intricately associated with aging, organ damage, frailty, and cognitive decline, resulting in a poor prognosis. The relationship among frailty, sarcopenia, cachexia, malnutrition, and heart failure has recently received considerable attention. Although these conditions are distinct, they often exhibit a remarkably close relationship. Overlapping diagnostic criteria have been observed in the recently proposed guidelines and position statements, suggesting that several of these conditions may coexist in patients with heart failure. Therefore, a comprehensive understanding of these conditions is essential, and interventions must not only target these conditions individually, but also provide comprehensive management strategies. This review article provides an overview of the epidemiology, diagnostic methods, overlap, and prognosis of frailty, sarcopenia, cachexia, and malnutrition in patients with heart failure, incorporating insights from the FRAGILE-HF study data. Additionally, based on existing literature, this article discusses the impact of these conditions on the effectiveness of guideline-directed medical therapy for patients with heart failure. While recognizing these conditions early and promptly implementing interventions may be advantageous, further data, particularly from well-powered, large-scale, randomized controlled trials, are necessary to refine personalized treatment strategies for patients with heart failure.

Adverse clinical events after percutaneous coronary intervention in very elderly patients with acute coronary syndrome.

The number of very elderly patients with acute coronary syndrome (ACS) is increasing. Therefore, owing to the need for evidence-based treatment decisions in this population, this study aimed to examine the clinical outcomes during 1 year after percutaneous coronary intervention (PCI) in very elderly patients with ACS. This prospective multicenter observational study comprised 1337 patients with ACS treated with PCI, classified into the following four groups according to age: under 60, <60 years; sexagenarian, ≥60 and <69 years; septuagenarian, ≥70 and <80 years; and very elderly, ≥80 years. The primary endpoint was a composite of the first occurrence of all-cause death, nonfatal myocardial infarction, nonfatal stroke, and bleeding within 1 year after PCI. We used the sexagenarian group as a reference and compared outcomes with those of the other groups. The incidence of the primary endpoint was significantly higher in the very elderly group than in the sexagenarian group (36 [12.7%] vs. 24 [6.9%], respectively; hazard ratio, 1.94; 95% confidence interval: 1.16-3.26; p = 0.012). The higher incidence of the primary endpoint was primarily driven by a higher incidence of all-cause death. When the multivariable analysis was used to adjust for patient characteristics and comorbidities, no difference was observed in the primary endpoint between the very elderly and sexagenarian groups (p = 0.96). The incidence of adverse events after PCI, particularly all-cause death, in very elderly patients with ACS was high. However, if several confounders are adjusted, comparable outcomes may be expected within 1 year after PCI among this population.

Prognostic value of weight loss in hospitalized patients with heart failure.

BACKGROUND: Weight loss is a poor prognostic factor in patients with chronic heart failure (HF). However, whether the same is true for hospitalized patients with HF is unknown, even though hospitalization is the first opportunity for many patients to be diagnosed with HF. This study aimed to investigate the prognostic value of weight loss in patients hospitalized for HF. METHODS: This was a post-hoc analysis of the FRAGILE-HF study, a prospective multi-center, observational study including 1,332 hospitalized older (≥65 years) patients with HF. The primary outcome was all-cause death within two years of discharge. RESULTS: Self-reported body weight data one year prior to hospital admission were available for 1,106 patients (83.0%) and were compared with their weight after decongestion therapy. The median weight change was -6.9% [-2.4 - -11.9] and 86.8% of the overall cohort experienced some weight loss. Whereas patients with weight loss ≥ 5%, which is a well-validated cut-off in chronic HF, had comparable mortality to those with less weight loss (p = 0.96 by log-rank test), patients with weight loss > 12%, the lowest quartile value, had higher mortality than those with less weight loss (p = 0.024 for all-cause mortality, p = 0.028 for non-cardiovascular mortality, and p = 0.28 for cardiovascular mortality, respectively). In a Cox proportional hazard model, > 12% weight loss was associated with high mortality after adjusting for known prognostic factors and history of malignancy (adjusted hazard ratio: 1.485 [1.070-2.062], p=0.018). CONCLUSION: Weight loss derived from patient-reported body weight one year before hospitalization was significantly associated with increased mortality after discharge, mainly due to non-cardiovascular etiology, in elderly patients hospitalized for HF.

Prognostically Optimal Heart Rate at Discharge in Hospitalized Patients With Heart Failure and Atrial Fibrillation.

Background: Managing heart rate (HR) is crucial for enhancing clinical prognosis in patients with heart failure (HF) and atrial fibrillation (AF). Nevertheless, the prognostic impact of HR at discharge in hospitalized HF patients remains unclear. Objectives: This study aimed to determine the HR associated with the lowest risk of death and HF in patients hospitalized with HF and AF. Methods: In this observational study, 334 persistent AF patients were analyzed from a database of 1,930 consecutive HF hospitalizations. Exclusion criteria included sinus rhythm or paroxysmal AF, cardiac pacemakers, or unrecorded HR at discharge. Participants were divided into four groups based on HR at discharge in 10 beats/min increments. The primary endpoint was a composite of death from any cause and rehospitalization due to HF. The association between resting HR and the primary endpoint was determined using Kaplan-Meier analysis and Cox proportional hazards models. Results: The median follow-up period was 389 days, with 133 patients (39.8%) reaching the primary endpoint. Kaplan-Meier analysis revealed a significantly higher primary endpoint incidence in patients with HR >81 beats/min at discharge compared to those with HR <60 beats/min (log-rank test for trend: P = 0.039). Multivariable Cox regression analysis showed that HR >81 beats/min at discharge was associated with the primary endpoint, with a hazard ratio of 1.79 (95% CI: 1.04-3.07), compared to HR <60 beats/min. Conclusions: The findings suggest that controlling HR to less than 80 beats/min at discharge may lead to better clinical outcomes in patients with HF and persistent AF.

Review of Bleeding and Thrombotic Risks Associated With Antithrombotic Therapy After Transcatheter Structural Heart Interventions.

Transcatheter structural heart interventions have drastically evolved over the past 2 decades. However, most catheterization procedures require the deployment of devices in the body; therefore, the adhesion of thrombi to those devices is a major problem, resulting in the requirement of a period of postprocedural antithrombotic regimen. However, in recent years, bleeding associated with these antithrombotic therapies has also become a major concern, attracting the attention of investigators. This is complicated by the fact that patients at high thrombotic risk are also at high bleeding risk, making the issue of administrating antithrombotic therapy challenging. The objective of this review was to identify the important issues and summarize the current status of postoperative antithrombotic therapy and assessment of the bleeding risk following transcatheter structural heart interventions such as transcatheter aortic valve replacement, transcatheter edge-to-edge repair, and transcatheter left atrial appendage occlusion.

Oral nutritional supplements in older outpatients with heart failure: rationale and design of the ALIMENT-HF trial.

AIMS: The ALIMENT-HF trial aims to determine whether high-calorie and high-protein oral nutritional supplements (ONS) are safe and beneficial for older adult outpatients with heart failure (HF). METHODS AND RESULTS: This multicentre, single-arm, interventional pilot trial is designed to evaluate the tolerance, efficacy, and safety of ONS in older adult outpatients with chronic HF, malnutrition, and anorexia. In total, 80 outpatients with HF regardless of their left ventricular ejection fraction will be treated with ONS, including high-energy (900 kcal/day) and high protein (36 g/day) supplementation, at eight sites in Japan. Inclusion criteria are as follows: age, ≥65 years; outpatients receiving maximally tolerated guideline-directed medical therapy for HF and without change in their diuretic dosage during the last 3 months; outpatients at risk of malnutrition, defined as a Malnutrition Universal Screening Tool score ≥1 point, and anorexia, defined using a Simplified Nutritional Appetite Questionnaire for the Japanese Elderly (SNAQ-JE) score of ≤14 points. Nutritional intervention will continue for up to 120 days, with an observational period lasting for a further 60 days. The primary outcome is a change in body weight between baseline and day 120. CONCLUSIONS: The ALIMENT-HF trial will evaluate the tolerance, efficacy, and safety of high-calorie and high-protein-rich ONS in older outpatients with HF co-morbid with malnutrition and anorexia and will provide insightful information for future randomized controlled trials.

Bendopnea prevalence and prognostic value in older patients with heart failure: FRAGILE-HF-SONIC-HF post hoc analysis.

AIMS: This study aimed to investigate the prevalence, clinical characteristics, and prognostic value of bendopnea in older patients hospitalized for heart failure. METHODS: This post hoc analysis was performed using two prospective, multicenter, observational studies: the FRAGILE-HF (main cohort) and SONIC-HF (validation cohort) cohorts. Patients were categorized based on the presence of bendopnea, which was evaluated before discharge. The primary endpoint was 2-year all-cause mortality after discharge. RESULTS: Among the 1,243 patients (median age, 81 years; 57.2% male) in the FRAGILE-HF cohort and 225 (median age, 79 years; 58.2% men) in the SONIC-HF cohort, bendopnea was observed in 31 (2.5%) and 10 (4.4%) patients, respectively. Over a 2-year follow-up period, all-cause death occurred in 20.8% and 21.9% of the patients in the FRAGILE-HF and SONIC-HF cohorts, respectively. Kaplan-Meier survival curves demonstrated significantly higher mortality rates in patients with bendopnea than in those without bendopnea in the FRAGILE-HF (log-rank P = 0.006) and SONIC-HF cohorts (log-rank P = 0.014). Cox proportional hazard analysis identified bendopnea as an independent prognostic factor for all-cause mortality in both the FRAGILE-HF (hazard ratio [HR] 2.11, 95% confidence interval [CI] 1.18-3.78, P = 0.012) and SONIC-HF cohorts (HR 4.20, 95% CI 1.63-10.79, P = 0.003), even after adjusting for conventional risk factors. CONCLUSIONS: Bendopnea was observed in a relatively small proportion of older patients hospitalized for heart failure before discharge. However, its presence was significantly associated with an increased risk of all-cause mortality.

This study investigated how common it is for older patients with heart failure to have trouble breathing when they bend forward, and whether this affects their chances of survival. The study found that although this problem is not very common, it is linked to a higher risk of death. Key findings: Only a small number of older patients with heart failure have trouble breathing when they bend forward.However, those who do have this problem are more likely to die.

Prognostic Value of Objective Social Isolation and Loneliness in Older Patients With Heart Failure: Subanalysis of FRAGILE-HF and Kitasato Cohort.

BACKGROUND: Social factors encompass a broad spectrum of nonmedical factors, including objective (social isolation [SI]) and perceived (loneliness) conditions. Although social factors have attracted considerable research attention, information regarding their impact on patients with heart failure is scarce. We aimed to investigate the prognostic impact of objective SI and loneliness in older patients with heart failure. METHODS AND RESULTS: This study was conducted using the FRAGILE-HF (Prevalence and Prognostic Value of Physical and Social Frailty in Geriatric Patients Hospitalized for Heart Failure; derivation cohort) and Kitasato cohorts (validation cohort), which included hospitalized patients with heart failure aged ≥65 years. Objective SI and loneliness were defined using the Japanese version of Lubben Social Network Scale-6 and diagnosed when the total score for objective and perceived questions on the Lubben Social Network Scale-6 was below the median in the FRAGILE-HF. The primary outcome was 1-year death. Overall, 1232 and 405 patients in the FRAGILE-HF and Kitasato cohorts, respectively, were analyzed. Objective SI and loneliness were observed in 57.8% and 51.4% of patients in the FRAGILE-HF and 55.4% and 46.2% of those in the Kitasato cohort, respectively. During the 1-year follow-up, 149 and 31 patients died in the FRAGILE-HF and Kitasato cohorts, respectively. Cox proportional hazard analysis revealed that objective SI, but not loneliness, was significantly associated with 1-year death after adjustment for conventional risk factors in the FRAGILE-HF. These findings were consistent with the validation cohort. CONCLUSIONS: Objective SI assessed using the Lubben Social Network Scale-6 may be a prognostic indicator in older patients with heart failure. Given the lack of established SI assessment methods in this population, further research is required to refine such methods.

Prognostic Impact of Sarcopenia Assessed Using Modified Asian Working Group for Sarcopenia 2019 Criteria in Heart Failure.

BACKGROUND: Sarcopenia is a substantial therapeutic target, yet the validity of risk stratification values per the latest Asian Working Group for Sarcopenia in 2019 (AWGS 2019) remains unconfirmed in patients with heart failure. We hypothesized that using the 6-minute walk test (6MWT) to assess physical performance improves risk stratification. METHODS: The study included 832 hospitalized patients with heart failure who could walk at discharge. Sarcopenia was diagnosed using both the original AWGS 2019 criteria (AWGS 2019 model) and an alternative method, in which physical performance components were replaced with the 6MWT (modified model). An <300 m 6MWT indicated low physical performance in the modified model. The primary outcome was 2-year mortality. RESULTS: Sarcopenia and severe sarcopenia were identified in 45 and 150 patients with the AWGS 2019 model and in 75 and 108 patients with the modified model, respectively. Over the 2-year follow-up period, 145 (17.4%) deaths occurred. Adjusted Cox proportional hazard analysis showed both sarcopenia and severe sarcopenia were significantly associated with 2-year mortality in the modified model. In the AWGS 2019 model, only severe sarcopenia was significantly related to 2-year mortality. The modified model demonstrated significant net reclassification improvement (NRI) over the AWGS 2019 model (NRI, 0.396; 95% CI, 0.214-0.578; P < 0.001). CONCLUSIONS: In patients with heart failure who were ambulatory at discharge, sarcopenia assessment with the modified AWGS 2019 model using the 6MWT as a physical performance component improved risk stratification compared with the original AWGS 2019 model. Reconsidering the current criteria to improve risk stratification is necessary to ensure timely, appropriate treatment.

Prognostic impact of MitraScore in elderly Asian patients with heart failure: sub-analysis of FRAGILE-HF.

AIMS: MitraScore is a novel, simple, and manually calculatable risk score developed as a prognostic model for patients undergoing transcatheter edge-to-edge repair (TEER) for mitral regurgitation. As its components are considered prognostic in heart failure (HF), we aimed to investigate the usefulness of the MitraScore in HF patients. METHODS AND RESULTS: We calculated MitraScore for 1100 elderly patients (>65 years old) hospitalized for HF in the prospective multicentre FRAGILE-HF study and compared its prognostic ability with other simple risk scores. The primary endpoint was all-cause deaths, and the secondary endpoints were the composite of all-cause deaths and HF rehospitalization and cardiovascular deaths. Overall, the mean age of 1100 patients was 80 ± 8 years, and 58% were men. The mean MitraScore was 3.2 ± 1.4, with a median of 3 (interquartile range: 2-4). A total of 326 (29.6%), 571 (51.9%), and 203 (18.5%) patients were classified into low-, moderate-, and high-risk groups based on the MitraScore, respectively. During a follow-up of 2 years, 226 all-cause deaths, 478 composite endpoints, and 183 cardiovascular deaths were observed. MitraScore successfully stratified patients for all endpoints in the Kaplan-Meier analysis (P < 0.001 for all). In multivariate analyses, MitraScore was significantly associated with all endpoints after covariate adjustments [adjusted hazard ratio (HR) (95% confidence interval): 1.22 (1.10-1.36), P < 0.001 for all-cause deaths; adjusted HR 1.17 (1.09-1.26), P < 0.001 for combined endpoints; and adjusted HR 1.24 (1.10-1.39), P < 0.001 for cardiovascular deaths]. The Hosmer-Lemeshow plot showed good calibration for all endpoints. The net reclassification improvement (NRI) analyses revealed that the MitraScore performed significantly better than other manually calculatable risk scores of HF: the GWTG-HF risk score, the BIOSTAT compact model, the AHEAD score, the AHEAD-U score, and the HANBAH score for all-cause and cardiovascular deaths, with respective continuous NRIs of 0.20, 0.22, 0.39, 0.39, and 0.29 for all-cause mortality (all P-values < 0.01) and 0.20, 0.22, 0.42, 0.40, and 0.29 for cardiovascular mortality (all P-values < 0.02). CONCLUSIONS: MitraScore developed for patients undergoing TEER also showed strong discriminative power in HF patients. MitraScore was superior to other manually calculable simple risk scores and might be a good choice for risk assessment in clinical practice for patients receiving TEER and those with HF.

Lymphocyte-to-C-reactive protein ratio and score in patients with heart failure: Nutritional status, physical function, and prognosis.

AIMS: In heart failure (HF), inflammation is linked to malnutrition and impaired physical function. In this study, we aimed to assess how novel nutritional-inflammatory markers and lymphocyte-to-C-reactive protein ratio (LCR) and score (LCS) are associated with the nutritional status, physical function, and prognosis of patients with HF. METHODS AND RESULTS: This study was a secondary analysis of the FRAGILE-HF study, a prospective observational study conducted across 15 hospitals in Japan. We included 1212 patients (mean age, 80.2 ± 7.8 years; 513 women) hospitalized with HF, who were classified into three groups according to their LCS score: 0 (n = 498), 1 (n = 533), and 2 (n = 181). Baseline data on physical examination, echocardiography, blood test results (including lymphocyte counts and CRP levels), and oral medication usage were collected in a clinically compensated state before discharge. Nutritional status and physical function were evaluated using several indices and tests. The primary outcome of this study was all-cause death within 2 years. Univariate and multivariate linear regression analyses were performed to evaluate the associations among the nutritional status, physical function, and LCR/LCS. Patients with an LCS score of 2 were older and had a lower body mass index than those in the other two groups. Multivariate linear regression analysis revealed that lower LCR and higher LCS were independently associated with worse nutritional status, lower handgrip strength, shorter physical performance battery score, and shorter 6-min walk distance. At 2 years, all-cause death occurred in 254 patients: 86 (17.6%), 113 (21.5%), and 55 (30.9%) with LCS scores of 0, 1, and 2, respectively (P = 0.001). Cox proportional hazards analysis revealed that LCR and LCS were significantly associated with 2-year mortality even after adjusting for the conventional risk model (LCS score, 0 vs. 2: hazard ratio, 1.64; 95% confidence interval [CI]; 1.14-2.35; P = 0.007; log-transformed LCR: hazard ratio, 0.88; 95% CI, 0.81-0.95; P = 0.002). LCR yielded additional prognostic predictability compared with the conventional risk model (continuous net reclassification improvement, 0.153; 95% CI, 0.007-0.299; P = 0.041). CONCLUSIONS: LCR and LCS emerge as potential predictors of nutritional status, physical function, and prognosis in older patients with HF.

Impact of Multidomain Frailty on the Mode of Death in Older Patients With Heart Failure: A Cohort Study.

BACKGROUND: Although frailty is strongly associated with mortality in patients with heart failure (HF), the risk of which specific cause of death is associated with being complicated with frailty is unclear. We aimed to clarify the association between multidomain frailty and the causes of death in elderly patients hospitalized with HF. METHODS: We analyzed data from the FRAGILE-HF cohort, where patients aged 65 years and older, hospitalized with HF, were prospectively registered between 2016 and 2018 in 15 Japanese hospitals before discharge and followed up for 2 years. All patients were assessed for physical, social, and cognitive dysfunction, and categorized into 3 groups based on their number of frailty domains (FDs, 0-1, 2, and 3). Kaplan-Meier survival analysis was used to evaluate the association between the number of FDs and all-cause mortality, whereas Fine-Gray competing risk regression analysis was used for assessing the impact on cause-specific mortality. RESULTS: We analyzed 1181 patients with HF (81 years old in median, 57.4% were male), 530 (44.9%), 437 (37.0%), and 214 (18.1%) of whom were categorized into the FD 0 to 1, FD 2, and FD 3 groups, respectively. During the 2-year follow-up, 240 deaths were observed (99 HF deaths, 34 cardiovascular deaths, and 107 noncardiovascular deaths), and an increase in the number of FD was significantly associated with mortality (Log-rank: P<0.001). The Fine-Gray competing risk analysis adjusted for age and sex showed that FDs 2 (subdistribution hazard ratio, 1.77 [95% CI, 1.11-2.81]) and 3 (2.78, [95% CI, 1.69-4.59]) groups were associated with higher incidence of noncardiovascular death but not with HF and other cardiovascular deaths. CONCLUSIONS: Although multidomain frailty is strongly associated with mortality in older patients with HF, it is mostly attributable to noncardiovascular death and not cardiovascular death, including HF death. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: UMIN000023929.