Publications by authors named "Masato Nakamura"

630 Publications

Changes in Antithrombotic Therapy Over Time and Durability of a Prasugrel WOEST-Like Regimen for Percutaneous Coronary Intervention Patients With Atrial Fibrillation - Post Hoc Analysis of the PENDULUM Mono and PENDULUM Registries.

Circ Rep 2022 May 21;4(5):194-204. Epub 2022 Apr 21.

Division of Cardiovascular Medicine, Toho University Ohashi Medical Center Tokyo Japan.

Previously published randomized atrial fibrillation (AF) percutaneous coronary intervention (PCI) trials have demonstrated the safety and efficacy of a WOEST-like regimen (oral anticoagulant [OAC] plus P2Y inhibitor) in patients with AF PCI within 1 year. However, the efficacy of this regimen in real-world practice has not been fully confirmed, especially the efficacy of the WOEST-like regimen using the approved dose of prasugrel in Japan. This post hoc analysis included 186 and 220 patients from the PENDULUM mono and PENDULUM registries, respectively. Endpoints were the cumulative incidences of clinically relevant bleeding (CRB) and major adverse cardiac and cerebrovascular events (MACCE) at 12 months after PCI. Differences in the enrollment period led to an increase in OAC prescriptions (from 64.7% to 81.2%) and a reduction in the median duration of triple antithrombotic therapy (from 203.0 to 32.0 days) in the PENDULUM vs. PENDULUM mono registries, respectively. After adjustment by the inverse probability of treatment method, in patients with OAC, PENDULUM mono AF significantly reduced CRB without increasing MACCE compared with PENDULUM AF. A WOEST-like regimen with prasugrel may reduce CRB, without increasing MACCE, in Japanese patients with AF and high bleeding risk undergoing PCI.
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http://dx.doi.org/10.1253/circrep.CR-22-0032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9072101PMC
May 2022

Efficacy and Safety of Prasugrel vs Clopidogrel in Thrombotic Stroke Patients With Risk Factors for Ischemic Stroke Recurrence: A Double-blind, Phase III Study (PRASTRO-III).

J Atheroscler Thromb 2022 May 21. Epub 2022 May 21.

Department of Neurological Science, Graduate School of Medicine, Nippon Medical School.

Aim: To examine the efficacy and safety of prasugrel vs clopidogrel in thrombotic stroke patients at risk of ischemic stroke.

Methods: This multicenter, active-controlled, randomized, double-blind, double-dummy, parallel group study enrolled thrombotic stroke patients aged ≥ 50 years at risk of ischemic stroke. Patients received prasugrel (3.75 mg/day) or clopidogrel (75 or 50 mg/day) for 24-48 weeks; other antiplatelet drugs were prohibited. The primary efficacy endpoint was the composite incidence of ischemic stroke, myocardial infarction (MI), and death from other vascular causes from the start to 1 day after treatment completion or discontinuation. Secondary efficacy endpoints included the incidences of ischemic stroke, MI, death from other vascular causes, ischemic stroke and transient ischemic attack, and stroke. Safety endpoints included bleeding events and adverse events (AEs).

Results: In the prasugrel (N=118) and clopidogrel (N=112; all received 75 mg) groups, the primary efficacy endpoint composite incidence (95% confidence interval) was 6.8% (3.0%-12.9%) and 7.1% (3.1%-13.6%), respectively. The risk ratio (prasugrel/clopidogrel) was 0.949 (0.369-2.443). Secondary efficacy endpoints followed a similar trend. The combined incidences of life-threatening, major, and clinically relevant bleeding were 5.0% and 3.5% in the prasugrel and clopidogrel groups, respectively. The incidences of all bleeding events and AEs were 19.2% and 24.6% and 76.7% and 82.5% in the prasugrel and clopidogrel groups, respectively. No serious AEs were causally related to prasugrel.

Conclusions: We observed a risk reduction of 5% with prasugrel vs clopidogrel, indicating comparable efficacy. There were no major safety issues for prasugrel.
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http://dx.doi.org/10.5551/jat.63473DOI Listing
May 2022

Overview of in-hospital outcomes in patients undergoing percutaneous coronary intervention with the revived directional coronary atherectomy.

Catheter Cardiovasc Interv 2022 May 20. Epub 2022 May 20.

Division of Cardiology, Tokai University School of Medicine, Isehara, Japan.

Objectives: We sought to provide clinical insights on the usage rate, indications, and in-hospital outcomes of the revived directional coronary atherectomy (DCA) catheter (Atherocut™) in a Japanese nationwide percutaneous coronary intervention (PCI) registry.

Background: Debulking devices such as the revived DCA catheter have become increasingly important in the era of complex PCI. However, little is known about PCI outcomes using a novel DCA catheter in contemporary real-world practice.

Methods: We analyzed 188,324 patients who underwent PCI in 1112 hospitals from January to December 2018. Baseline characteristics and in-hospital outcomes of patients with stable coronary artery disease or unstable angina who underwent PCI with or without the DCA were analyzed.

Results: Overall, 1696 patients (0.9%) underwent PCI with the DCA during the study period, predominantly for left main trunk or proximal left anterior descending artery lesions under a transfemoral approach. Patients in the DCA group were younger and had fewer comorbidities such as hypertension, diabetes mellitus, and chronic kidney disease than patients in the non-DCA group. Stentless PCI using the DCA with drug-coated balloon angioplasty was a preferred treatment strategy in the DCA group (50.0%). Predefined in-hospital adverse outcomes, including mortality (0.2% vs. 0.3%, p = 0.446) and periprocedural complications (1.8% vs. 1.7%, p = 0.697), were comparable between the two groups, whereas the fluoroscopy time was longer and the total contrast volume was higher in the DCA group.

Conclusions: In Japan, PCI using the revived DCA catheter is safely performed with low complication rates in patients with stable coronary artery disease or unstable angina.
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http://dx.doi.org/10.1002/ccd.30233DOI Listing
May 2022

Early P2Y Inhibitor Single Antiplatelet Therapy for High-Bleeding Risk Patients After Stenting - PENDULUM Mono 24-Month Analysis.

Circ J 2022 May 17. Epub 2022 May 17.

Division of Cardiovascular Medicine, Toho University Ohashi Medical Center.

Background: In PENDULUM mono, Japanese patients with high bleeding risk (HBR) received short-term dual antiplatelet therapy (DAPT) followed by single antiplatelet therapy (SAPT) with prasugrel after percutaneous coronary intervention (PCI). One-year data from PENDULUM mono showed better outcomes with prasugrel monotherapy after short-term DAPT compared with matched patients in the PENDULUM registry with longer DAPT durations according to guidelines at that time. This study presents 2-year results.Methods and Results: We compared 24-month data from PENDULUM mono (n=1,107; de-escalation strategy group) and the PENDULUM registry (n=2,273; conventional strategy group); both were multicenter, non-interventional, prospective registry studies, using the inverse probability of treatment weighting (IPTW) method. In the PENDULUM mono group, the cumulative incidence of clinically relevant bleeding (CRB) at 24 months post-PCI (primary endpoint) was 6.8%, and that of major adverse cardiac and cerebrovascular events (MACCE) was 8.9%. After IPTW adjustment, the cumulative incidence of CRB was 5.8% and 7.2% in PENDULUM mono and the PENDULUM registry, respectively (hazard ratio [HR] 0.77; 95% confidence interval [CI] 0.57-1.04; P=0.086), and that of MACCE was 8.0% and 9.5%, respectively (HR 0.77; 95% CI 0.59-1.01; P=0.061).

Conclusions: Japanese PCI patients with HBR prescribed prasugrel SAPT after short-term DAPT had a lower ischemic event risk than those prescribed long-term DAPT, and this was particularly relevant for ischemic events after 1 year.
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http://dx.doi.org/10.1253/circj.CJ-21-1004DOI Listing
May 2022

Clinical Outcomes After Percutaneous Coronary Intervention in East Asian Patients - 30-Month Results of the PENDULUM Registry.

Circ J 2022 May 13. Epub 2022 May 13.

Division of Cardiovascular Medicine, Toho University Ohashi Medical Center.

Background: The 12-month results of the PENDULUM registry showed that after implantation of second-generation drug-eluting stents (DES), high P2Yreaction unit (HPR) were independently associated with ischemic but not bleeding events.Methods and Results: This study analyzed cumulative incidences of major adverse cardiac and cerebrovascular events (MACCE) and major bleeding (Bleeding Academic Research Consortium type 3 and 5) at 30 months after index percutaneous coronary intervention (PCI) (primary endpoints). Of 6,422 patients undergoing PCI with DES, 5,796 completed the 30-month follow up. The continuation rate of dual antiplatelet therapy decreased to 59.3% at 12 months and 26.4% at 30 months. At 30 months, the cumulative incidence of MACCE increased linearly and reached 9.5% (95% confidence interval 8.8-10.2) and that of major bleeding had the inflection point at 12 months and was 4.4% (3.9-5.0). MACCE and bleeding events were higher in HPR patients (unadjusted P value). After covariate adjustment, P2Yreactivity units measured immediately after index PCI was not an independent risk factor for MACCE or major bleeding at 30 months.

Conclusions: MACCE consistently increased after 12 months post-PCI, whereas the increase in major bleeding events slowed down after 12 months in Japanese PCI patients in a real-world clinical setting. HPR patients had increased MACCE and bleeding complications, but HPR was not an independent risk factor of events at 30 months.
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http://dx.doi.org/10.1253/circj.CJ-21-0991DOI Listing
May 2022

Clinical use of physiological lesion assessment using pressure guidewires: an expert consensus document of the Japanese association of cardiovascular intervention and therapeutics-update 2022.

Cardiovasc Interv Ther 2022 May 11. Epub 2022 May 11.

Department of Cardiology, Tokai University Hospital, Isehara, Japan.

Fractional flow reserve and instantaneous wave-free ratio are widely accepted and recommended in Western and Japanese guidelines for appropriate percutaneous coronary intervention. There are, however, many differences in clinical situations between Japan and Western countries. Therefore, the Task Force on coronary physiology of the Japanese Association of Cardiovascular Intervention and Therapeutics (CVIT) has proposed an expert consensus document to summarize current evidence and suggest the practical use of physiological lesion assessment in Japan.
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http://dx.doi.org/10.1007/s12928-022-00863-1DOI Listing
May 2022

Final Analysis of 3 Versus 6 Months of Adjuvant Oxaliplatin and Fluoropyrimidine-Based Therapy in Patients With Stage III Colon Cancer: The Randomized Phase III ACHIEVE Trial.

J Clin Oncol 2022 May 5:JCO2102628. Epub 2022 May 5.

Tokai University School of Medicine, Isehara, Japan.

Purpose: The phase III ACHIEVE trial conducted in Japan was one of six prospective studies included in the International Duration Evaluation of Adjuvant Therapy collaboration, which explored whether 3 months of adjuvant fluorouracil, leucovorin, and oxaliplatin (FOLFOX) or capecitabine and oxaliplatin (CAPOX) therapy would be noninferior to 6 months of treatment in patients with curatively resected stage III colon cancer. We report the final analyses of survival and long-term safety.

Patients And Methods: Eligible patients were randomly assigned (1:1) to either 3 or 6 months of adjuvant chemotherapy (modified [m]FOLFOX6 or CAPOX, as selected by the treating physician). Random assignment was stratified according to number of involved lymph nodes, center, regimen, primary site, and age. The primary end point was disease-free survival, assessed in the modified intention-to-treat population. Overall survival (OS) was a secondary end point.

Results: The modified intention-to-treat population comprised 1,291 patients: 641 in the 6-month treatment group and 650 in the 3-month treatment group. Median follow-up for this analysis was 74.7 months. Five-year OS rates were comparable: 87.0% in the 3-month treatment group and 86.4% in the 6-month treatment group (hazard ratio, 0.91; 95% CI, 0.69 to 1.20; = .51). Subgroup analysis of OS did not reveal a significant interaction between baseline characteristics and treatment duration. Peripheral sensory neuropathy lasting longer than 5 years was more common in the 6- compared with 3-month treatment group (16% 8%, respectively), and in those receiving mFOLFOX6 compared with CAPOX (14% 11%, respectively).

Conclusion: In Asian patients, shortening adjuvant therapy duration from 6 to 3 months did not compromise efficacy and reduced the rate of long-lasting peripheral sensory neuropathy. In this setting, 3 months of CAPOX therapy is an appropriate adjuvant treatment option.
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http://dx.doi.org/10.1200/JCO.21.02628DOI Listing
May 2022

Evaluation of the effect of nitric oxide inhalation in the patients with chronic thromboembolic pulmonary hypertension or pulmonary disease during balloon pulmonary angioplasty.

Pulm Circ 2022 Jan 18;12(1):e12032. Epub 2022 Jan 18.

Division of Cardiovascular Medicine Toho University Ohashi Medical Center Tokyo Japan.

Balloon pulmonary angioplasty (BPA) for chronic thromboembolic pulmonary hypertension (CTEPH) or pulmonary disease (CTEPD) is performed worldwide. High mean pulmonary arterial pressure (mPAP) during BPA is associated with aggravation of procedure-related complications. Inhaled nitric oxide (NO) acts as a pulmonary vasodilator in CTEPH patients. The aim of this retrospective observational study was to evaluate the effects of inhaled NO in CTEPH/CTEPD patients during BPA. We assessed hemodynamic changes and the frequency of procedure-related complications with or without NO inhalation. We performed 338 consecutive BPA in 72 CTEPH/CTEPD patients between April 2016 and November 2020. Since December 2019, all 16 patients (72-BPA sessions) inhaled NO during the procedure as a routine. Inhaled NO significantly reduced mPAP from 31.3 ± 8.5 to 27.2 ± 6.8 mmHg ( < 0.001) without lowering systemic blood pressure (systolic: 139.9 ± 19.9 vs. 135.3 ± 21.8 mmHg;  = 0.247, diastolic: 82.8 ± 13.0 vs. 79.0 ± 9.3 mmHg;  = 0.085, before vs. after NO inhalation, respectively). Procedure-related complications were observed in 46 sessions (13.6%). The incidence of hemoptysis was significantly higher in the NO group than in the non-NO group (20.8% vs. 10.9%;  = 0.031). In contrast, all fatal complications (death and use of positive pressure ventilation) occurred in the non-NO group, but the difference was not statistically significant (0 sessions [0.0%] vs. 7 sessions [2.6%],  = 0.353). Inhaled NO acts as a selective pulmonary vasodilator in CTEPH/CTEPD patients during the BPA procedure.
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http://dx.doi.org/10.1002/pul2.12032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9053008PMC
January 2022

Impact and safety of balloon pulmonary angioplasty for elderly patients.

Pulm Circ 2022 Jan 3;12(1):e12009. Epub 2022 Jan 3.

Division of Cardiovascular Medicine Toho University Ohashi Medical Center Tokyo Japan.

Recently, balloon pulmonary angioplasty (BPA) for chronic thromboembolic pulmonary hypertension (CTEPH) and chronic thromboembolic pulmonary disease (CTEPD) has become an established procedure with stable results. The number of elderly CTEPH/CTEPD patients has also increased due to the widespread recognition of the disease concept. However, the reports of BPA in the elderly are limited. The aim of this study was to evaluate the efficacy and safety of BPA in elderly patients (>80 years). From April 2016 to December 2020, 344 BPA sessions (74 patients) were performed. The safety and efficacy of the BPA procedures were compared in the younger group (<80 years; 278 sessions) and the elderly group (≥80 years; 66 sessions). The hemodynamic parameters were significantly improved in both groups (mean pulmonary arterial pressure: 34.4 ± 9.9 → 21.2 ± 6.2 mmHg,  < 0.001 and 33.2 ± 9.6 → 21.8 ± 8.5 mmHg,  < 0.001; pulmonary vascular resistance: 474.5 ± 248.6 → 201.3 ± 108.7 dyne sec cm,  < 0.001 and 496.4 ± 290.9 → 260.5 ± 120.2 dyne sec cm,  = 0.002, in younger and elderly group, respectively). The rate of death within 30 days of BPA (0.3% vs. 0%,  = 1.000) and use of positive pressure ventilation (1.4% vs. 3.0%,  = 0.600) were not different between the groups (younger vs. elderly, respectively). BPA significantly improved the hemodynamic parameters of elderly CTEPH/CTEPD patients, and the safety is comparable to that of younger patients.
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http://dx.doi.org/10.1002/pul2.12009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9053002PMC
January 2022

Initial Safety Analysis of CapeOx for Elderly Patients With Advanced Gastric Cancer Patients: A Phase II Trial.

Anticancer Res 2022 May;42(5):2683-2687

Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan.

Background: Safety of combination chemotherapy using platinum and fluorouracil has not been evaluated adequately for advanced gastric cancer (AGC) in elderly patients.

Patients And Methods: We initiated a phase II study to evaluate the efficacy and safety of capecitabine plus oxaliplatin (CapeOX) as first-line therapy for patients with AGC aged ≥70 years. Planned assessment of toxicity was made upon recruitment of the first 20 patients.

Results: In five out of 20 patients, unacceptable toxicity was observed, including three patients who were unable to complete the initial two courses due to adverse events. Among the other 15 patients, dose reduction due to toxicity were needed in 10 and treatment delay for adverse events also occurred in 12 patients during the first two courses.

Conclusion: Early analyses of safety suggest that the CapeOX regimen was not tolerated without dose reduction for elderly patients with AGC in this study.
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http://dx.doi.org/10.21873/anticanres.15746DOI Listing
May 2022

Phase II Study of S-1 and Irinotecan Plus Bevacizumab as Second-line Treatment for Patients With Metastatic Colorectal Cancer Resistant to the Fluoropyrimidine-oxaliplatin-cetuximab Regimen.

Anticancer Res 2022 May;42(5):2675-2681

Department of Digestive Surgery, Nihon University Itabashi Hospital, Tokyo, Japan.

Background/aim: The usefulness of angiogenesis inhibitors as second-line treatment after the progression of anti-epidermal growth factor receptor antibody drug-containing regimens for RAS wild-type metastatic colorectal cancer (mCRC) has not been fully investigated. Therefore, we conducted a phase II study to verify the efficacy and safety of the combination of S-1 and irinotecan plus bevacizumab (SIRB regimen) as second-line treatment for patients with oxaliplatin and cetuximab-refractory KRAS wild-type mCRC.

Patients And Methods: Patients with mCRC who had previously received oxaliplatin and cetuximab-containing regimen were eligible for this study. Patients were infused with bevacizumab 7.5 mg/kg and irinotecan 150 mg/m intravenously on day 1, whereas S-1 80 mg/m was administered orally twice daily until day 15, followed by a 7-day drug holiday period. The primary end point was 6-month progression-free survival (PFS) rate.

Results: In total, 17 patients were enrolled in this study. The 6-month PFS rate was 64.7% [95% confidence interval (CI)=41.99-87.43], median PFS was 10.1 months (95%CI=4.11-17.28), and median overall survival was 21.8 months (95%CI=9.79-37.91). The response rate was 23.5% (95%CI=6.81-49.90%). Grade ≥3 adverse events were observed in 10% of patients, and included leukopenia [3 (17.6%)], neutropenia [5 (29.4%)], anorexia [2 (11.8%)], diarrhea [2 (11.8%)], and hypertension [3 (17.6%)]. No treatment-related deaths or febrile neutropenia were observed.

Conclusion: The SIRB regimen might be a promising second-line treatment option for patients with oxaliplatin and cetuximab-refractory KRAS wild-type mCRC in terms of efficacy and safety.
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http://dx.doi.org/10.21873/anticanres.15745DOI Listing
May 2022

Independent Predictors of Major Adverse Cardiovascular Events at 3 Years after Aortoiliac Stent Implantation.

J Vasc Interv Radiol 2022 Apr 7. Epub 2022 Apr 7.

Division of Cardiovascular Medicine, Toho University, Ohashi Medical Center, Tokyo, Japan.

Purpose: To identify the risk factors for major adverse cardiovascular events (MACEs) in real-world practice for symptomatic peripheral artery disease in Japan.

Materials And Methods: Data on Japanese patients (N = 880) from the Observational Prospective Multicenter Registry Study on Outcomes of Peripheral Arterial Disease Patients Treated by Angioplasty Therapy for Aortoiliac Artery who underwent de novo aortoiliac stent placement. The 3-year risk of incident MACEs was investigated.

Results: The median age of the patients was 72.6 years (range, 34-97 years), and 83.1% of the patients were men. The patients had the following conditions: smoking (35.6%), hypertension (94.1%), dyslipidemia (81.7%), diabetes (48.0%), renal failure on dialysis (12.6%), myocardial infarction (12.7%), stroke (15.8%), and chronic limb-threatening ischemia (7.1%). Femoropopliteal lesions were present in 38.8% of the limbs with aortoiliac lesions. The 3-year rate of freedom from MACEs was 89.1%. Baseline characteristics, such as age, renal failure on dialysis, myocardial infarction, stroke, and femoropopliteal lesions, were independently associated with the risk of incident MACEs. When the study population was stratified according to these risk factors, the rate of MACEs was highest in patients with at least 3 risk factors (32.9% at 3 years).

Conclusions: The 3-year rate of freedom from MACEs was reported. Baseline characteristics, such as age, renal failure on dialysis, myocardial infarction, stroke, and femoropopliteal lesions, are independent risk factors for MACEs after aortoiliac stent placement.
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http://dx.doi.org/10.1016/j.jvir.2022.03.602DOI Listing
April 2022

Durvalumab with or without tremelimumab combined with particle therapy for advanced hepatocellular carcinoma with macrovascular invasion: protocol for the DEPARTURE phase Ib trial.

BMJ Open 2022 Apr 8;12(4):e059779. Epub 2022 Apr 8.

National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.

Introduction: Advanced hepatocellular carcinoma (HCC) with macrovascular invasion (MVI) has the worst prognosis among all phenotypes. This trial aims to evaluate whether treatment with durvalumab, alone or in combination with tremelimumab, plus particle therapy is a safe and synergistically effective treatment in patients with advanced HCC and MVI.

Methods And Analysis: This phase Ib, multicentre (two sites in Japan), open-label, single-arm, investigator-initiated clinical trial will assess durvalumab monotherapy in combination with particle therapy (cohort A) and that of durvalumab plus tremelimumab in combination with particle therapy (cohort B) for patients with advanced HCC with MVI. Cohort A will receive 1500 mg durvalumab every 4 weeks. Cohort B will receive 1500 mg durvalumab every 4 weeks in principle and 300 mg tremelimumab only on day 1 of the first cycle. Carbon-ion radiotherapy will be administered after day 8 of the first cycle. The primary endpoints are rates of any and severe adverse events, including dose-limiting toxicities (DLTs); secondary endpoints are overall survival, 6-month survival, objective response, 6-month progression-free survival and time to progression. Patients are initially enrolled into cohort A. If cohort A treatment is confirmed to be tolerated (ie, no DLT in three patients or one DLT in six patients), the trial proceeds to enrol more patients into cohort B. Similarly, if cohort B treatment is confirmed to be tolerated (ie, no DLT in three patients or one DLT in six patients), a total of 15 patients will be enrolled into cohort B.

Ethics And Dissemination: This study was approved by the ethics committees of the two participating institutions (Chiba University Hospital and National Institutes for Quantum (approval number: 2020040) and Radiological Science and Technology, QST Hospital (approval number: C20-001)). Participants will be required to provide written informed consent. Trial results will be reported in a peer-reviewed journal publication.

Trial Registration Number: jRCT2031210046.
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http://dx.doi.org/10.1136/bmjopen-2021-059779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8995959PMC
April 2022

Preprocedural frailty is strongly associated with symptoms after balloon pulmonary angioplasty.

Glob Health Med 2022 Feb;4(1):45-51

Division of Cardiovascular Medicine, Toho University Ohashi Medical Center, Tokyo, Japan.

Balloon pulmonary angioplasty (BPA) has improved the survival rate of patients with chronic thromboembolic pulmonary hypertension (CTEPH). The resolution of symptoms is one of the remaining goals of BPA. Frailty affects the outcome of cardiovascular diseases or treatments. The aim of this study is to assess the association between frailty and outcome of BPA. The resolution of symptoms is evaluated by the post-BPA World Health Organization functional class (WHO-FC). A total of 54 patients with CTEPH were divided into 2 groups by post-BPA WHO-FC (WHO-FC I group; = 34 WHO-FC ≥ II group; = 20). Frailty was assessed by physicians using the clinical frailty scale (CFS) at the point of patient admission for their first BPA sessions. Compared to the WHO-FC ≥ II group, the WHO-FC I group was younger (65.6 ± 13.9 years 74.3 ± 8.0 years) and had a lower CFS (3 [3, 4] 4 [4, 6]) (median [25th, 75th percentiles]). The WHO-FC I achievement rates for each CFS score were CFS 3: 82.8%; 4: 53.8%; 5: 25.0%; 6: 33.3%; and 7: 20.0%. Logistic regression analysis showed that CFS was an independent predictor of WHO-FC I achievement (odds ratio 0.50, = 0.012), but pre-BPA hemodynamic parameters and age were not independent predictors. Whether WHO-FC I can be achieved is predicted by pre-BPA patient frailty but not by pre-BPA hemodynamic parameters and age.
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http://dx.doi.org/10.35772/ghm.2021.01019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8884035PMC
February 2022

Evolution of Survival Impact of Molecular Target Agents in Patients with Advanced Hepatocellular Carcinoma.

Liver Cancer 2022 Jan 6;11(1):48-60. Epub 2021 Dec 6.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Background And Aims: The prognosis of patients with advanced hepatocellular carcinoma (HCC) is expected to improve as multiple molecular target agents (MTAs) are now available. However, the impact of the availability of sequential MTAs has not been fully verified yet.

Approach And Results: We retrospectively collected the data on the whole clinical course of 877 patients who received any MTAs as first-line systemic therapy for advanced HCC between June 2009 and March 2019. The study population was divided into 3 groups according to the date of first-line MTA administration (period 1: 2009-2012, = 267; period 2: 2013-2016, = 352; period 3: 2017-2019, = 258). Then, we compared the number of MTAs used, overall survival (OS), and MTA treatment duration among the 3 groups. Analysis was also performed separately for advanced-stage and nonadvanced-stage HCC. The proportion of patients who received multiple MTAs was remarkably increased over time (1.1%, 10.2%, and 42.6% in periods 1, 2, and 3, respectively, < 0.001). The median OS times were prolonged to 10.4, 11.3, and 15.2 months in periods 1, 2, and 3, respectively ( = 0.016). Similarly, the MTA treatment durations were extended (2.7, 3.2, and 6.6 months in periods 1, 2, and 3, respectively; < 0.001). We confirmed that the correlation between OS and MTA treatment duration was strengthened (period 1: 0.395, period 2: 0.505, and period 3: 0.667). All these trends were pronounced in the patients with advanced-stage HCC but limited in the patients with nonadvanced-stage HCC.

Conclusions: The availability of multiple MTAs had steadily improved the prognosis of patients with advanced HCC patients, particularly advanced-stage HCC patients.
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http://dx.doi.org/10.1159/000519868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8820147PMC
January 2022

The impact of kidney function in patients on antithrombotic therapy: a post hoc subgroup analysis focusing on recurrent bleeding events from the AFIRE trial.

BMC Med 2022 02 25;20(1):69. Epub 2022 Feb 25.

Kumamoto University, 2-39-1 Kurokami, Chuo-ku, Kumamoto, 860-8555, Japan.

Background: The success of antithrombotic therapies is assessed based on thrombotic and bleeding events. Simultaneously assessing both kinds of events might be challenging, and recurrent bleeding events are often ignored. We tried to confirm the effects of kidney function on outcome events in patients undergoing antithrombotic therapy.

Methods: As a post hoc subgroup analysis of the Atrial Fibrillation and Ischemic Events with Rivaroxaban in Patients with Stable Coronary Artery Disease (AFIRE) trial, a randomized clinical trial with a median follow-up of 36 months, patients were divided into high and low estimated glomerular filtration rate (eGFR) groups with a cutoff value of 50 mL/min. The cumulative incidence of bleeding and crude incidence of recurrent bleeding per 100 patient-years were calculated. We used the Cox regression model with multiple failure time data for recurrent bleeding events.

Results: Among 2092 patients, 1386 (66.3%) showed high eGFR. The cumulative bleeding events per 100 patients at 1 year were 5.4 and 6.2 in the high and low eGFR groups, respectively. The difference continued to increase over time. The hazard ratio for time to the first bleeding event in the high eGFR group was 0.875 (95% confidence interval 0.701-1.090, p = .234) and that for the first composite event was 0.723 (95% confidence interval 0.603-0.867, p < .000). The recurrent bleeding events per 100 person-years were 11.3 and 15.3 in the high and low eGFR groups, respectively, with a rate ratio of 0.738 (95% confidence interval 0.615-0.886, p = .001). During the observation period, the risk of bleeding changed with time. It peaked soon after the study enrollment in both groups. It decreased continuously in the high eGFR group but remained high in the low eGFR group.

Conclusions: We reaffirmed that kidney function affects bleeding events in patients on antithrombotic therapy, considering recurrent events. Patients should have detailed discussions with physicians regarding the possible bleeding events when continuing antithrombotic therapy, especially in patients with decreased kidney function.

Trial Registration: UMIN Clinical Trials Registry, UMIN000016612 . ClinicalTrials.gov, NCT02642419 . Registered on 21 October 2015.
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http://dx.doi.org/10.1186/s12916-022-02268-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8876785PMC
February 2022

Impact of acute decompensation on the prognosis of patients with hepatocellular carcinoma.

PLoS One 2022 27;17(1):e0261619. Epub 2022 Jan 27.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Background/aims: Organ failure in patients with acute decompensation (AD) is a defining characteristic of acute-on-chronic liver failure (ACLF). However, the clinical features of AD during the long-term clinical course of hepatocellular carcinoma (HCC) are still poorly understood. This study aimed to clarify features and impact of AD/ACLF on the prognosis of patients after treatment for HCC.

Methods: This retrospective study enrolled 556 consecutive patients who were initially diagnosed with HCC, and analyses were conducted taking into account HCC treatment type, HCC stage, and presence or absence of cirrhosis.

Results: During follow-up, 299 patients with AD were hospitalized. AD occurrence is closely related to prognosis, regardless of the presence or absence of cirrhosis and HCC stage, and early-onset AD (within 90 days after HCC treatment) has negative impact on prognosis. In the intermediate-advanced-stage group, surgical resection had a positive impact on AD incidence post-treatment. After systemic therapy for HCC, renal impairment was the predictive factors for AD development. The 28/90-day mortality rate was higher among 41 cases (13.7%) with AD who exhibited ACLF as compared with cases without ACLF. AD without cirrhosis had similar ACLF incidence and short-term mortality, compared to AD with cirrhosis. The prognostic model using a decision-tree-based approach, which includes ACLF, bilirubin level, HCC progression, and MELD score is useful for predicting 90- or 28-day mortality after AD diagnosis.

Conclusions: Careful management of patients with HCC who are hospitalized with AD is necessary, considering ACLF, HCC progression, and liver function.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0261619PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8794202PMC
February 2022

Multi-tumor analysis of cancer-stroma interactomes of patient-derived xenografts unveils the unique homeostatic process in renal cell carcinomas.

iScience 2021 Nov 21;24(11):103322. Epub 2021 Oct 21.

Department of Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Experimental Research Buliding, 12Floor, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8654, Japan.

The patient-derived xenograft (PDX) model is a versatile tool used to study the tumor microenvironment (TME). However, limited studies have described multi-tumor PDX screening strategies to detect hub regulators during cancer-stroma interaction. Transcriptomes of cancer (human) and stroma (mouse) components of 70 PDX samples comprising 9 distinctive tumor types were analyzed in this study. PDX models recapitulated the original tumors' features, including tumor composition and putative signaling. Particularly, kidney renal clear cell carcinoma (KIRC) stood out, with altered hypoxia-related pathways and a high proportion of endothelial cells in the TME. Furthermore, an integrated analysis conducted to predict paracrine effectors in the KIRC cancer-to-stroma communication detected well-established soluble factors responsible for the hypoxia-related reaction and the so-far unestablished soluble factor, apelin (APLN). Subsequent experiments also supported the potential role of APLN in KIRC tumor progression. Therefore, this paper hereby provides an analytical workflow to find hub regulators in cancer-stroma interactions.
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http://dx.doi.org/10.1016/j.isci.2021.103322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8767947PMC
November 2021

Cost-effectiveness of 12 months of capecitabine as adjuvant chemotherapy for stage III colon cancer: preplanned cost-effectiveness analysis of the JFMC37-0801 study.

Eur J Health Econ 2022 Jan 24. Epub 2022 Jan 24.

Center for Outcomes Research and Economic Evaluation for Health, National Institute of Public Health, Saitama, Japan.

Objectives: We evaluated the cost-effectiveness of a 12-month regimen of oral capecitabine versus a standard 6-month regimen as postoperative adjuvant chemotherapy for stage III colon cancer.

Methods: We utilized patient-level data from a multi-institutional randomized controlled trial (JFMC37-0801) that investigated prolonged oral fluoropyrimidine monotherapy. The analysis considered three health states: stable disease, post-metastasis, and death. A parametric statistical model with a cure model was used to estimate the survival curve. The analysis was conducted from the Japanese public healthcare payer's perspective, considering only direct medical costs. A lifetime horizon was used, with a discount rate of 2% for both cost and health outcomes. Health outcomes were evaluated in terms of quality-adjusted life-years (QALYs).

Results: The estimated cure rates for colon cancer were 0.726 [95% confidence interval (CI) 0.676-0.776] and 0.694 (95% CI 0.655-0.733) with the 12- and 6-month regimens, respectively; and the estimated 5-year relapse-free survival rates were 74.4% and 69.8%, respectively. The estimated lifetime cost for 12 months of capecitabine was JPY 3.365 million (USD 31,159), compared with JPY 3.376 million (USD 31,262) for 6 months. The estimated QALY were 12.48 and 11.77 for the 12- and 6-month regimens, respectively. Thus, the 12-month capecitabine regimen was dominant. Using a willingness-to-pay threshold of JPY 5 million per QALY, we determined a 97.4% probability that the 12-month capecitabine regimen is more cost-effective than the 6-month regimen.

Conclusions: Twelve months of capecitabine is the favorable option for postoperative adjuvant chemotherapy for stage III colon cancer from the perspective of cost-effectiveness.
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http://dx.doi.org/10.1007/s10198-021-01418-6DOI Listing
January 2022

CVIT expert consensus document on primary percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI) update 2022.

Cardiovasc Interv Ther 2022 Jan 12;37(1):1-34. Epub 2022 Jan 12.

The Cardiovascular Institute, Tokyo, Japan.

Primary Percutaneous Coronary Intervention (PCI) has significantly contributed to reducing the mortality of patients with ST-segment elevation myocardial infarction (STEMI) even in cardiogenic shock and is now the standard of care in most of Japanese institutions. The Task Force on Primary PCI of the Japanese Association of Cardiovascular Interventional and Therapeutics (CVIT) society proposed an expert consensus document for the management of acute myocardial infarction (AMI) focusing on procedural aspects of primary PCI in 2018. Updated guidelines for the management of AMI were published by the European Society of Cardiology (ESC) in 2017 and 2020. Major changes in the guidelines for STEMI patients included: (1) radial access and drug-eluting stents (DES) over bare-metal stents (BMS) were recommended as a Class I indication, (2) complete revascularization before hospital discharge (either immediate or staged) is now considered as Class IIa recommendation. In 2020, updated guidelines for Non-ST-Elevation Myocardial Infarction (NSTEMI) patients, the followings were changed: (1) an early invasive strategy within 24 h is recommended in patients with NSTEMI as a Class I indication, (2) complete revascularization in NSTEMI patients without cardiogenic shock is considered as Class IIa recommendation, and (3) in patients with atrial fibrillation following a short period of triple antithrombotic therapy, dual antithrombotic therapy (e.g., DOAC and single oral antiplatelet agent preferably clopidogrel) is recommended, with discontinuation of the antiplatelet agent after 6 to 12 months. Furthermore, an aspirin-free strategy after PCI has been investigated in several trials those have started to show the safety and efficacy. The Task Force on Primary PCI of the CVIT group has now proposed the updated expert consensus document for the management of AMI focusing on procedural aspects of primary PCI in 2022 version.
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http://dx.doi.org/10.1007/s12928-021-00829-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8789715PMC
January 2022

One-year outcome after percutaneous coronary intervention in nonagenarians: Insights from the J-PCI OUTCOME registry.

Am Heart J 2022 04 10;246:105-116. Epub 2022 Jan 10.

Department of Cardiovascular Medicine, Tokai University, Isehara, Japan.

Background: Nonagenarian patients who undergo percutaneous coronary intervention (PCI) are increasing, and a few previous studies have reported their long-term outcomes. However, differences in their long-term outcomes between generations remain unclear. This study aimed to investigate 1-year all-cause and cardiovascular (CV) mortality, and major adverse cardiovascular events (MACE; cardiovascular death, myocardial infarction, and stroke) of nonagenarian patients who underwent PCI compared with the other elder patients, using a nationwide registration system.

Methods: The patient-level data registered between January 2017 and December 2017 was extracted from the J-PCI OUTCOME Registry endorsed by the Japanese Association of Cardiovascular Intervention and Therapeutics (CVIT). The one-year all-cause and cardiovascular (CV) mortality, MACE, and major bleeding events were identified.

Results: Out of 40,722 patients over 60 years of age, 880 (2.1%) were nonagenarians. For nonagenarians, the 1-year mortality rate was substantial (13.5%). The MACE and CV death rates were also high (8.1%, and 6.8%, respectively) for nonagenarians, and these event rates were approximately 1.5 times higher in nonagenarians than octogenarians. Multivariate regression analysis showed that presentation with cardiogenic shock [hazard ratio (HR) 2.32; 95 confidence intervals (CI): 1.22-4.41], or cardiac arrest (HR 2.91; 90% CI: 1.28-6.62), and use of oral anticoagulants (HR 2.10; 90% CI: 1.07-4.12) were the predictors of 1-year MACE.

Conclusions: Even in the contemporary era, nonagenarians who have undergone PCI still face a considerably increased risk for adverse cardiovascular events that reduces long-term survival. In addition to having poorer lesion characteristics, adverse events, including death, MACEs, and major bleeding, occurred 1.5 times more frequently in nonagenarians than in octogenarians.
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http://dx.doi.org/10.1016/j.ahj.2022.01.004DOI Listing
April 2022

Relationship between platelet aggregation and stroke risk after percutaneous coronary intervention: a PENDULUM analysis.

Heart Vessels 2022 Jun 1;37(6):942-953. Epub 2022 Jan 1.

Division of Cardiovascular Medicine, Toho University Ohashi Medical Center, Tokyo, Japan.

In patients undergoing percutaneous coronary intervention (PCI) with a stent, high on-treatment platelet reactivity may be associated with an increased risk of stroke. This post hoc analysis of the PENDULUM registry compared the risk of post-PCI stroke according to on-treatment P2Y reaction unit (PRU) values. Patients aged ≥ 20 years who underwent PCI were stratified by baseline PRU (at 12 and 48 h post-PCI) as either high (HPR, > 208), optimal (OPR, > 85 to ≤ 208), or low on-treatment platelet reactivity (LPR, ≤ 85). The incidences of non-fatal ischemic and non-ischemic stroke through to 12 months post-PCI were recorded. Almost all enrolled patients (6102/6267 [97.4%]) had a risk factor for ischemic stroke, and most were receiving dual antiplatelet therapy. Of the 5906 patients with PRU data (HPR, n = 2227; OPR, n = 3002; LPR, n = 677), 47 had a non-fatal stroke post-PCI (cumulative incidence: 0.68%, ischemic; 0.18%, non-ischemic stroke). Patients with a non-fatal ischemic stroke event had statistically significantly higher post-PCI PRU values versus those without an event (P = 0.037). The incidence of non-fatal non-ischemic stroke was not related to PRU value. When the patients were stratified by PRU ≤ 153 versus > 153 at 12-48 h post-PCI, a significant difference was observed in the cumulative incidence of non-fatal stroke at 12 months (P = 0.044). We found that patients with ischemic stroke tended to have higher PRU values at 12-48 h after PCI versus those without ischemic stroke.Clinical trial registration: UMIN000020332.
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http://dx.doi.org/10.1007/s00380-021-02003-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9114031PMC
June 2022

Response to letter to editor from Dr. Adam Ioannou.

QJM 2021 Dec 21. Epub 2021 Dec 21.

Department of Cardiovascular Medicine, Toho University Ohashi Medical Center, Tokyo, Japan.

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http://dx.doi.org/10.1093/qjmed/hcab327DOI Listing
December 2021

Ischemic and Bleeding Events in PENDULUM Patients With High Bleeding Risk and High Platelet Reactivity.

Circ J 2022 04 8;86(5):763-771. Epub 2021 Dec 8.

Division of Cardiovascular Medicine, Toho University Ohashi Medical Center.

Background: The balance between thrombotic and bleeding risk is of great concern in high bleeding risk (HBR) patients. This study evaluated the relationship between perioperative antiplatelet reactivity and thrombotic and bleeding events in patients at HBR undergoing percutaneous coronary intervention (PCI).Methods and Results: In this post hoc analysis of the PENDULUM (Platelet rEactivity in patieNts with DrUg eLUting stent and balancing risk of bleeding and ischeMic event) registry, patients undergoing PCI were categorized as HBR or non-HBR, and stratified as having high platelet reactivity (HPR; P2Yreaction unit [PRU] >208) or non-HPR (PRU ≤208). Cumulative incidences of cardiovascular and cerebrovascular events (Journal of the American College of Cardiology expert definitions) and bleeding events (Bleeding Academic Research Consortium criteria) were assessed 12 months after index PCI. The incidence of ischemic and bleeding events was ~3-fold higher in HBR vs. non-HBR patients. Thrombotic/ischemic events were significantly more common in the HPR subgroup in HBR patients (hazard ratio [HR]: 1.59; 95% confidence interval [CI]: 1.11-2.28; P=0.012), but there was no difference in non-HBR patients. After adjustment for covariates, HPR in HBR patients remained an independent factor for thrombotic and ischemic events (HR: 1.69; 95% CI: 1.13-2.54; P=0.011), but not for bleeding events (HR: 1.56; 95% CI: 0.78-3.11; P=0.210).

Conclusions: Maintaining adequate PRU levels during PCI is an important factor in improving clinical outcomes, especially for HBR patients.
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http://dx.doi.org/10.1253/circj.CJ-21-0717DOI Listing
April 2022
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