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Background: Low-gradient (LG) aortic stenosis (AS) has not been fully characterized compared with high-gradient (HG) AS in terms of cardiac damage, frailty, aortic valve calcification, and clinical outcomes., Objectives: The aim of this study was to compare the clinical characteristics and outcomes between each hemodynamic type of LG AS and HG AS., Methods: The current study included 3,363 patients in the CURRENT AS (Contemporary outcomes after sURgery and medical tREatmeNT in patients with severe Aortic Stenosis) Registry-2 after excluding patients without indexed stroke volume or left ventricular ejection fraction (LVEF) data. Patients were divided into 4 groups (LG AS with reduced LVEF: n = 285; paradoxical low flow, low gradient [LFLG]: n = 220; normal flow, low gradient [NFLG]: n = 872; HG: n = 1,986)., Results: Compared with HG AS, LG AS with reduced LVEF more often had cardiovascular comorbidities, advanced cardiac damage, and frailty with less severe valve calcification and paradoxical LFLG AS more often had atrial fibrillation, advanced cardiac damage, and frailty with less severe valve calcification, while NFLG AS had comparable cardiac damage and frailty with less severe valve calcification. Cumulative 3-year incidence of death or heart failure hospitalization was higher in LG AS with reduced LVEF and paradoxical LFLG than in HG AS. After adjusting for confounders, LG AS with reduced LVEF and paradoxical LFLG compared with HG AS were independently associated with higher risk for death or heart failure hospitalization (HR: 1.82; 95% CI: 1.49-2.23; P < 0.001; and HR: 1.43; 95% CI: 1.13-1.82; P = 0.003, respectively) but NFLG AS was not (HR: 1.03; 95% CI: 0.88-1.21; P = 0.68)., Conclusions: Clinical outcomes were significantly worse in LG AS with reduced LVEF and paradoxical LFLG AS and comparable in NFLG AS compared with HG AS., Competing Interests: Funding Support and Author Disclosures This work was supported by an educational grant from the Research Institute for Production Development (Kyoto, Japan). Dr Shirai has served as a clinical proctor for Edwards Lifesciences, Medtronic, and Abbott. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2025. Published by Elsevier Inc.)

Recent advances in traditional "-omics" technologies have provided deeper insights into cardiovascular diseases through comprehensive molecular profiling. Accordingly, digitalomics has emerged as a novel transdisciplinary concept that integrates multimodal information with digitized physiological data, medical imaging, environmental data, electronic health records, environmental records, and biometric data from wearables. This digitalomics-driven augmented multiomics approach can provide more precise personalized health risk assessments and optimization when combined with conventional multiomics approaches. Artificial intelligence and machine learning (AI/ML) technologies, alongside statistical methods, serve as key comprehensive analytical tools in realizing this comprehensive framework. This review focuses on two promising AI/ML applications in cardiovascular medicine: digital phonocardiography (PCG) and AI text generators. Digital PCG uses AI/ML models to objectively analyze heart sounds and predict clinical parameters, potentially surpassing traditional auscultation capabilities. In addition, large language models, such as generative pretrained transformer, have demonstrated remarkable performance in assessing medical knowledge, achieving accuracy rates exceeding 80% in medical licensing examinations, although there are issues regarding knowledge accuracy and safety. Current challenges to the implementation of these technologies include maintaining up-to-date medical knowledge and ensuring consistent accuracy of outputs, but ongoing developments in fine-tuning and retrieval-augmented generation show promise in addressing these challenges. Integration of AI/ML technologies in clinical practice, guided by appropriate validation and implementation strategies, may notably advance precision cardiovascular medicine through the digitalomics framework.

Background: Heart failure (HF) hospitalization is increasing in Japan's aging population. Current guidelines recommend daily biometric monitoring for patients with HF to facilitate early clinical intervention. However, promoting patient self-management remains insufficient. Therefore, we assessed the usefulness of the LAVITA telemonitoring system, which automatically obtains and stores the biometric data of patients with HF via wireless devices., Methods and Results: This prospective, single-arm, multicenter cohort study enrolled patients with HF. Patients were introduced to the LAVITA telemonitoring system and trained to measure body weight, blood pressure, pulse rate, oxygen saturation (SpO 2 ), physical activity with activity trackers (AT), and electronic patient-reported outcomes (ePRO). The primary outcome was the measurement rate of each cetology at 9-12 weeks post-discharge. The secondary outcomes included the subgroup analyses by age, sex, and left ventricular function. Thirty patients continued to use the system at home. The measurement rates of patient data were as follows: body weight 92.4% (interquartile range [IQR] 83.3-97.8%); blood pressure 95.6% (IQR 84.8-98.5%); pulse rate 96.5% (IQR 86.5-98.8%); SpO 2 93.1% (IQR 76.6-97.9%); AT 88.4% (IQR 31.3-98.5%); and ePRO 76.9% (IQR 26.4-95.9%). The subgroup analysis did not significantly differ., Conclusions: The LAVITA telemonitoring system had high measurement rates for the biometric data of patients with HF, including elderly patients. Hence, it can possibly improve patient self-management and facilitate early clinical intervention., Competing Interests: The present study was conducted under a collaborative research agreement with Nihon Kohden Corporation, which provided a joint research grant. The authors declare that although Nihon Kohden Corporation supported this study, the authors had full independence in reporting the study results., (Copyright © 2025, THE JAPANESE CIRCULATION SOCIETY.)

There was a scarcity of data evaluating variations in treatment approaches and clinical outcomes for severe aortic stenosis (AS) between medical centers with and without availability of transcatheter aortic valve implantation (TAVI). Current study population was 2993 patients with severe AS enrolled in the CURRENT AS Registry-2 (2581 patients from 10 TAVI centers; 412 patients from 10 non-TAVI centers). TAVI centers more frequently opted for the initial aortic valve replacement (AVR) strategy compared to non-TAVI centers (60% and 40%, P < 0.001). Among patients with the initial AVR strategy, TAVI centers disproportionately favored the initial TAVI strategy compared to non-TAVI centers (71% and 23%, P < 0.001). No significant differences were observed in the risk of a composite of all-cause death or heart failure hospitalization between TAVI and non-TAVI centers in the entire study population (cumulative 3-year incidence: 32.0% and 31.0%, P = 0.37; adjusted hazard ratios: 0.92, 95% confidence intervals: 0.74-1.15, P = 0.45) or in conservative, initial AVR, initial surgical AVR, and initial TAVI strata. A substantial disparity exists in the treatment strategies for patients with severe AS between TAVI and non-TAVI centers. TAVI centers tended to perform AVR, particularly TAVI, earlier and more frequently. However, there was no discernible distinction in the risk of the composite of all-cause death or HF hospitalization between TAVI and non-TAVI centers. UMINID: UMIN000034169., Competing Interests: Declarations. Conflict of interest: K. Ono and K. Minatoya are members of Circulation Journal’s Editorial Team. S.S. reports clinical proctoring for Edwards Life Science, Medtronic, and Abbott Vascular. H.S. reports receiving personal fees from Abbott Vascular, Boston Scientific, and Daiichi Sankyo. T.M reports receiving lecturer fees from Bristol-Myers Squibb, Daiichi Sankyo, Japan Lifeline, Kowa, Kyocera, Novartis, and Toray and manuscript fees from Bristol-Myers Squibb and Kowa, as well as being on the advisory board for Sanofi. T. Kimura reports being on the advisory board for Abbott Vascular and receiving grants from Edwards Lifescience, Daiichi Sankyo, Takeda Pharmaceutical, Bayer, Otsuka Parmaceutical, Boehringer Ingelheim, Mitsubishi Tanabe Pharma, Sumitomo Dainippon Pharma, Kowa, Abiomed, Japan Academic Research Forum, NIPRO, W.L. Gore & Associates G.K., RPM Co., Ltd., CSL Behring, Pfizer R&D Japan G.K., and EP- CRSU Co., Ltd; and honoraria from MSD, Eisai, Edwards Lifescience, Ono Pharmaceutical, Tsumura, Medical Review, Kowa, Sanofi, Pharmaceuticals and Medical Devices Agency, Bristol-Myers Squibb, Boston Scientific, Lifescience, Toray, Astellas Amgen Biopharma, Astellas, AstraZeneca, OrbusNeich, MSD Life Science Foundation, Public Health Research Foundation, Chugai Pharmaceutical, Japan Society for the Promotion of Science, Interscience, Philips, Kowa Pharmaceutical, Mitsubishi Tanabe Pharma, Terumo, Novartis Pharma, HeartFlow Japan G.K., and CROSSCO Co. The remaining authors have no conflicts of interest to disclose. IRB information: The present study was approved by Kyoto University Graduate School and Faculty of Medicine Ethics Committee, Reference number: R1501., (© 2024. The Author(s) under exclusive licence to Japanese Association of Cardiovascular Intervention and Therapeutics.)

Objective: Lipoprotein (a) (Lp[a]), which is a highly heritable trait, is associated with coronary artery disease (CAD). However, the insight into whether the association between Lp(a) and CAD differs according to the family history of CAD remains unclear., Methods: We investigated clinical data of 4,512 participants who underwent serum Lp(a) level measurement at Kanazawa University Hospital between 2008 and 2016. The association between Lp(a) and CAD according to CAD family history was investigated through logistic regression analyses., Results: CAD family history and Lp(a) levels were significantly associated with CAD development (odds ratio [OR], 1.32; 95% confidence interval [CI], 1.12-1.52; p <0.001 and OR, 1.13; 95% CI, 1.03-1.23; p <0.001 per 10 mg/dL, respectively). In patients without CAD family history, those with Lp(a) levels ≥30 mg/dL had higher CAD risk than those with Lp(a) levels <30 mg/dL (reference) (OR, 1.33; 95% CI, 1.05-1.61; p <0.001). In patients with CAD family history, those who had Lp(a) levels <30 and ≥30 mg/dL were both highly at risk for CAD (OR, 1.24; 95% CI, 1.04-1.44; p <0.001 and OR, 1.68; 95% CI, 1.34-2.02; p <0.001, respectively). Adding CAD family history and Lp(a) information to other conventional risk factors enhanced CAD risk discrimination (C-statistics: 0.744 [0.704-0.784] to 0.768 [0.730-0.806], and 0.791 [0.751-0.831], respectively; p <0.05 for both)., Conclusion: Lp(a) level was associated with CAD development regardless of CAD family history status., Competing Interests: Conflict of Interest: The authors have no conflicts of interest to declare., (© 2025 The Korean Society of Lipid and Atherosclerosis.)

The relation between Body Mass Index (BMI) and adverse outcomes after endovascular therapy (EVT) for patients with lower extremity artery disease (LEAD) remains incompletely understood. From April 2010 to March 2020, 199 consecutive patients who underwent EVT for LEAD were retrospectively analyzed. The patients were divided into three groups based on BMI; underweight < 18.5 kg/m 2 , normal weight ≥ 18.5 and < 25.0 kg/m 2 , and overweight ≥ 25.0 kg/m 2 . The endpoint of this study was a composite of all-cause mortality, major amputation, and major bleeding. Patients who were underweight often exhibited anemia (53.3 vs. 22.3 vs. 15.4%, respectively; p = 0.001) and severe chronic kidney disease (50.0 vs. 30.8 vs. 20.5%, respectively; p = 0.03). Furthermore, these patients had higher incidences of Trans-Atlantic Inter-Society Consensus class C or D lesions (40.0 vs. 20.0 vs. 10.3%, respectively; p = 0.01). During the median follow-up duration of 3.6 years (interquartile range: 1.2 to 6.7 years), there were 73 incidents of the composite endpoint. When the overweight group was assigned as the reference group, the adjusted hazard ratios for the composite endpoint for the underweight and normal weight patients were 3.67 (95% confidence interval [CI] 1.39-10.83, p = 0.008) and 2.35 (95% CI 1.06-6.23, p = 0.03), respectively. Kaplan-Meier curve demonstrated that the freedom from the composite endpoint for underweight, normal weight, and overweight patients was 41.6%, 60.0%, 83.8%, respectively (p < 0.001). These results suggest that there was an inverse association between BMI and adverse outcomes composed of mortality, limb amputation, and bleeding in patients with LEAD undergoing EVT., Competing Interests: Declarations. Conflict of interest: The authors declare that they have no conflict of interest., (© 2024. The Author(s) under exclusive licence to Japanese Association of Cardiovascular Intervention and Therapeutics.)

Aims: Little data exists for evaluating the prevalence and patient characteristics of familial hypercholesterolemia (FH) according to the latest 2022 guidelines for FH published by the Japan Atherosclerosis Society (JAS), which revised the Achilles tendon thickness (ATT) threshold from 9.0 mm in both sexes to 8.0 mm in men and 7.5 mm in women. This study used a nationwide registry of patients with acute coronary syndrome (ACS) to evaluate the prevalence of FH according to the latest diagnostic criteria for FH and to investigate the application of Achilles tendon imaging in the diagnosis of FH.A previous prospective observational study at 59 Japanese centers involving consecutive patients with ACS who were managed between April 2015 and August 8, 2016 was conducted to explore lipid management and persistent risk in patients hospitalized for ACS (EXPLORE-J). The study population consisted of 1,944 EXPLORE-J enrollees., Results: According to the diagnostic criteria for FH in the 2022 JAS guidelines, the prevalence of probable or definite was among patients with ACS was 6.6% (127/1944). Among patients with premature ACS (male, age ＜55 years; female, age ＜65 years), the prevalence of FH was 10.1% (43/427). The mean ages were of the probable FH and definite FH groups were 59.9 and 61.0 years, respectively, while the mean age of the possible-or-unlikely FH group was 66.4 years (significantly older). Relative to the possible-or-unlikely FH group, the low-density lipoprotein cholesterol (LDL-C) levels were similar in the probable FH group and and significantly higher in the definite FH group., Conclusions: The prevalence of FH was considerably higher than previously reported, especially for patients with premature ACS. The age and LDL-C levels of the patients in the probable FH and definite FH groups were similar.

Background: There is a paucity of data on safety of calcium channel blockers (CCB) in patients with severe aortic stenosis (AS) and hypertension., Methods and Results: Among 2,460 patients with severe AS and hypertension receiving antihypertensive therapy in the CURRENT AS registry-2, we compared the clinical outcomes between patients taking antihypertensive therapy with CCB (CCB group) and without CCB (no CCB group). In the entire study population, CCB was prescribed in 1,763 patients (71.7%), which was the most commonly prescribed antihypertensive agents. The prescription rates of angiotensin converting enzyme inhibitors or angiotensin receptor blockers, beta-blockers, and thiazides were 61.9%, 25.6%, and 7.3% in the CCB group, and 75.8%, 54.4%, and 6.0% in the no CCB group. In the propensity score matched cohort, the cumulative 3-year incidence of all-cause death or hospitalization for heart failure was not different between the CCB and no CCB groups (38.3% vs. 38.7%, log-rank P=0.65; HR, 0.94; 95%CI, 0.77-1.15; P=0.56). The cumulative 3-year incidence of syncope was low regardless of CCB prescription (1.1% vs. 1.0%, P=0.74)., Conclusions: Among patients with severe AS and hypertension, CCB was the most commonly prescribed antihypertensive agents, and antihypertensive therapy with CCB was associated with comparable clinical outcomes to antihypertensive therapy without CCB. Syncope was rarely seen in patients with severe AS and hypertension receiving antihypertensive therapy regardless of CCB prescription.

Hypertension has been associated with worse outcomes in patients with familial hypercholesterolemia (FH). We aimed to identify the clinical impact of blood pressure management on the development of cardiovascular events. We assessed patients with clinically diagnosed heterozygous FH (n = 1,273, male/female = 614/659) with blood pressure data. We categorized them into 4 groups (group 1: patients without hypertension from baseline to follow-up; group 2: patients without hypertension at baseline but in whom hypertension developed at follow-up; group 3: patients with hypertension at baseline that was well-controlled at follow-up; group 4: patients with hypertension from baseline that was uncontrolled at follow-up). We used Cox proportional hazards models to evaluate factors associated with cardiovascular events, including cardiovascular death and any coronary events. The median follow-up period was 10.9 years. We observed 142 cardiovascular events during the follow-up period and revealed that blood pressure management was significantly associated with cardiovascular event occurrence (hazard ratio [HR] 2.50, 95% confidence interval [CI] 1.30 to 3.70, p <0.001; HR 4.18, 95% CI 2.08 to 6.28, p <0.001; HR 10.96, 95% CI 6.10 to 17.58, p <0.001 in groups 2, 3, and 4, respectively, with group 1 as reference). In conclusion, blood pressure management is crucial in patients with heterozygous FH., Competing Interests: Declaration of competing interest The authors have no competing interest to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Data on concomitant mitral regurgitation (MR) in patients with severe aortic stenosis (AS) are scarce., Methods and results: We investigated the risk of concomitant MR in patients with severe AS in the CURRENT AS Registry-2 according to initial treatment strategy (transcatheter aortic valve implantation [TAVI], surgical aortic valve replacement [SAVR], or conservative). Among 3,365 patients with severe AS, 384 (11.4%) had moderate/severe MR (TAVI: n=126/1,148; SAVR: n=68/591; conservative: n=190/1,626). The cumulative 3-year incidence for death or heart failure (HF) hospitalization was significantly higher in the moderate/severe than no/mild MR group in the entire population (54.6% vs. 34.3%, respectively; P<0.001) and for each treatment strategy (TAVI: 45.0% vs. 31.8% [P=0.006]; SAVR: 31.9% vs. 18.7% [P<0.001]; conservative: 67.8% vs. 41.6% [P<0.001]). The higher adjusted risk of moderate/severe MR relative to no/mild MR for death or HF hospitalization was not significant in the entire population (hazard ratio [HR] 1.15; 95% confidence interval [CI] 0.95-1.39; P=0.15); however, the risk was significant in the SAVR (HR 1.92; 95% CI 1.04-3.56; P=0.04) and conservative (HR 1.30; 95% CI 1.02-1.67; P=0.04) groups, but not in the TAVI group (HR 1.03; 95% CI 0.70-1.52; P=0.86), despite no significant interaction (P interaction =0.37)., Conclusions: Moderate/severe MR was associated with a higher risk for death or HF hospitalization in the initial SAVR and conservative strategies, while the association was less pronounced in the initial TAVI strategy.

Background: There is a scarcity of data on the prevalence of abnormal findings on preprocedural computed tomography (CT) before aortic valve replacement (AVR) in patients with aortic stenosis (AS)., Methods: Among consecutive 593 patients with severe AS who were planned to undergo AVR, we evaluated the prevalence of clinically significant incidental noncardiac findings on preprocedural CT. Clinically significant incidental noncardiac findings were defined as newly detected abnormalities that required therapy, consultation for expert, further investigation, or clinical follow-up., Results: The mean age was 82.0 years and 39.5 % of the patients were men. Of those, 78.4 % of the patients were treated with transcatheter aortic valve implantation (TAVI) and 21.6 % of the patients were treated with surgical AVR (SAVR). There were 271 clinically significant incidental noncardiac findings in 227 patients (38.3 %) including 2.5 % of malignancy. The prevalence of clinically significant incidental noncardiac findings were higher in the TAVI group than in the SAVR group (40.2 % versus 31.3 %). The prevalence of clinically significant incidental noncardiac findings were lower in patients under 60 years of age (10.0 %) than in patients over 60 years of age (60-69 years: 40.0 %, 70-79 years: 34.3 %, 80-89 years: 39.7 %, and ≥90 years: 42.1 %)., Conclusions: Clinically significant incidental noncardiac findings were newly identified on preprocedural CT in approximately 40 % of patients with severe AS undergoing AVR including 2.5 % of malignancy., Competing Interests: Declaration of competing interest Kenji Minatoya is a member of the editorial team of Circulation Journal., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Intervention for severe aortic stenosis (AS) has dramatically progressed since the introduction of transcatheter aortic valve replacement (TAVR). Decades ago, controversies existed regarding comparing clinical outcomes between TAVR and surgical aortic valve replacement (SAVR) in various risk profiles. Recently, we discussed the durability of transcatheter heart valves and their lifetime management after aortic valve replacement (AVR). Regarding the management of AS, we discuss the appropriate timing of intervention for severe aortic stenosis, especially in asymptomatic patients. In spite of dramatic progression of intervention for AS, there are no established medications available to prevent or slow the progression of AS at present. Basic research and genome studies have suggested several targets associated with the progression of aortic valve calcification. Randomized controlled trials evaluating the efficacy of medications to prevent AS progression are ongoing, which might lead to new strategies for AS management. In this review, we summarize the current management of AS and the drugs expected to prevent the progression of AS.

Background: There is a scarcity of data on the prevalence and clinical impact of cerebrovascular disease detected on preprocedural computed tomography (CT) before aortic valve replacement (AVR) in patients with severe aortic stenosis., Methods and Results: Among patients with severe aortic stenosis undergoing AVR, the authors compared clinical outcomes between patients with and without cerebrovascular disease detected on preprocedural CT, which was defined as chronic brain infarction or hemorrhage. The primary outcome measure in this study was a composite of all-cause death or stroke. Among 567 study patients, 200 patients (35.3%) had cerebrovascular disease on preprocedural CT. Among 200 patients with cerebrovascular disease on preprocedural CT, only 28.5% of patients had a clinical history of symptomatic stroke. The cumulative 3-year incidence of death or stroke was higher in patients with cerebrovascular disease on preprocedural CT than in those without cerebrovascular disease on preprocedural CT (40.7% versus 24.1%, log-rank P <0.001). After adjusting for confounders, the higher risk of patients with cerebrovascular disease on preprocedural CT relative to those without remained significant for death or stroke (hazard ratio [HR], 1.42 [95% CI, 1.02-1.98]; P =0.04). Among 200 patients with cerebrovascular disease on preprocedural CT, patients with prior symptomatic stroke compared with those without were not associated with higher adjusted risk for death or stroke (HR, 1.18 [95% CI, 0.72-1.94]; P =0.52)., Conclusions: Among patients with severe aortic stenosis undergoing AVR, a substantial proportion had cerebrovascular disease on preprocedural CT, with a clinical history of symptomatic stroke in one-fourth of patients. Regardless of history of symptomatic stroke, patients with cerebrovascular disease on preprocedural CT had worse clinical outcomes compared with those without cerebrovascular disease on preprocedural CT.

Background: Polypharmacy was reported to be associated with major bleeding in various populations. However, there are no data on polypharmacy and its association with bleeding in patients undergoing percutaneous coronary intervention (PCI)., Methods and results: Among 12,291 patients in the CREDO-Kyoto PCI Registry Cohort-3, we evaluated the number of medications at discharge and compared major bleeding, defined as Bleeding Academic Research Consortium Type 3 or 5 bleeding, across tertiles (T1-3) of the number of medications. The median number of medications was 6, and 88.0% of patients were on ≥5 medications. The cumulative 5-year incidence of major bleeding increased incrementally with increasing number of medications (T1 [≤5 medications] 12.5%, T2 [6-7] 16.5%, and T3 [≥8] 20.4%; log-rank P<0.001). After adjusting for confounders, the risks for major bleeding of T2 (hazard ratio [HR] 1.21; 95% confidence interval [CI] 1.08-1.36; P=0.001) and T3 (HR 1.27; 95% CI 1.12-1.45; P<0.001) relative to T1 remained significant. The adjusted risks of T2 and T3 relative to T1 were not significant for a composite of myocardial infarction or ischemic stroke (HR 0.95 [95% CI 0.83-1.09; P=0.47] and HR 1.06 [95% CI 0.91-1.23; P=0.48], respectively)., Conclusions: In a real-world population of patients undergoing PCI, approximately 90% were on ≥5 medications. Increasing number of medications was associated with a higher adjusted risk for major bleeding, but not ischemic events.

Background: Achilles tendon thickening (ATT) can be ameliorated by lowering low-density lipoprotein (LDL) levels in patients with familial hypercholesterolemia (FH). The Japan Atherosclerosis Society (JAS) defines ATT as ≥8.0 mm in males and ≥7.5 mm in females. We aimed to determine the clinical impact of changes in ATT on the development of major adverse cardiovascular events (MACE)., Methods: Patients with clinically diagnosed heterozygous FH (HeFH) ( N = 1273; 614 males, 659 females) with ATT data from X-ray were assessed. Patients were divided into four groups: patients without ATT from baseline until follow-up (group 1), patients without ATT at baseline but developed ATT at follow-up (group 2), patients with ATT at baseline but regressed at follow-up (group 3), and patients with ATT from baseline until follow-up (group 4). Cox proportional hazard models were used to assess the factors associated with MACE, including cardiovascular death and any coronary events., Results: On follow-up (median: 10.9 years), 142 MACEs were observed, and the median ATT regressed from 7.8 to 7.6 mm. Changes in ATT were significantly associated with the occurrence of MACE in all groups, when compared to group 1 (hazard ratio [HR]: 2.73; 95 % confidence interval [CI]: 1.33-4.13 [ p < 0.001], HR: 2.18, 95 % CI: 1.08-3.28, [ p < 0.001], HR: 6.34, 95 % CI: 3.10-9.58, [ p < 0.001], in groups 2, 3, and 4, respectively)., Conclusions: Assessing ATT has diagnostic value and allows for risk stratification among patients with HeFH., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Background: Familial hypercholesterolemia (FH) is associated with atherosclerotic cardiovascular disease (ASCVD). However, the prevalence of FH among a general population remains unknown, and it is unclear if FH is associated with other cardiovascular complications, including heart failure (HF) and atrial fibrillation (AF)., Methods: Analyses were conducted on individuals without a prior history of cardiovascular disease using a nationwide health claims database collected in the JMDC Claims Database between 2005 and 2022 (n = 4,126,642; median age, 44 years; 57.5% men). We defined FH as either LDL cholesterol ≥250 mg/dL or LDL cholesterol ≥175 mg/dL under the lipid-lowering medications under the assumption that lipid-lowering medications reduced LDL cholesterol by 30%. We assessed the associations between FH and composite outcomes, including, ASCVD (myocardial infarction, angina pectoris, and stroke), HF, and AF using Cox proportional hazard model., Results: We identified 11,983 (.29%) FH patients. In total, 181,150 events were recorded during the mean follow-up period of 3.5 years. The status FH was significantly associated with composite outcomes after adjustments (hazard ratio [HR]; 1.38, 95% confidence interval [CI]: 1.30-1.47, p < .001). Interestingly, the status FH was significantly associated with HF (HR: 1.48, 95% CI: 1.36-1.61, p < .001) and AF (HR: 1.33, 95% CI: 1.08-1.64, p < .001) in addition to angina pectoris (HR: 1.45, 95% CI: 1.33-1.58, p < .001) and stroke (HR: 1.19, 95% CI: 1.04-1.36, p < .001)., Conclusion: We found that the prevalence of FH was .29% in a general population. FH was significantly associated with a higher risk of developing cardiovascular disease, HF and AF., Lay Summary: We sought to identify the prevalence of FH among a general population, and to clarify whether FH increases the risk of not only ASCVD but also HF and AF., (© 2023 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

There were no data comparing the in-hospital outcomes after transcatheter aortic valve implantation (TAVI) with those after surgical aortic valve replacement (SAVR) in Japan. Among consecutive patients with severe AS between April 2018 and December 2020 in the CURRENT AS Registry-2, we identified 1714 patients who underwent aortic valve replacement (TAVI group: 1134 patients, and SAVR group: 580 patients). Patients in the TAVI group were much older (84.4 versus 73.6 years, P < 0.001) and more often had comorbidities than those in the SAVR group. In-hospital death rate was numerically lower in the TAVI group than in the SAVR group (0.6% versus 2.2%). After excluding patients with dialysis, in-hospital death rate was very low and comparable in the TAVI and SAVR groups (0.6% versus 0.8%). The rates of major bleeding and new-onset atrial fibrillation during index hospitalization were higher after SAVR than after TAVI (72% versus 20%, and 26% versus 4.6%, respectively), while the rate of pacemaker implantation was higher after TAVI than after SAVR (8.1% versus 2.4%). Regarding the echocardiographic data at discharge, the prevalence of patient-prosthesis mismatch was lower in the TAVI group than in the SAVR group (moderate: 9.0% versus 26%, and severe: 2.6% versus 4.8%). In this real-world data in Japan, TAVI compared with SAVR was chosen in much older patients with more comorbidities with severe AS. In-hospital death rate was numerically lower in the TAVI group than in the SAVR group., (© 2023. The Author(s).)

Background: It remains unclear if remnant cholesterol is associated with atherosclerotic cardiovascular disease (ASCVD) (myocardial infarction, angina pectoris and stroke), heart failure (HF), and atrial fibrillation (AF) under primary prevention settings., Objective: We aimed to clarify this issue among a general population without a history of ASCVD, HF or AF., Methods: Analyses were conducted with a nationwide health claims database collected in the JMDC Claims Database between 2005 and 2022 (n = 1,313,722; median age, 42 years; 54.6% men). We assessed the associations between remnant cholesterol calculated as total cholesterol minus HDL cholesterol minus LDL cholesterol and composite CVD outcomes, including, ASCVD, HF, and AF using Cox proportional hazard model, dividing the individuals into tertiles of remnant cholesterol (T1-T3)., Results: The mean follow-up duration was 3.0 years. In total, 43,755 events were recorded. Remnant cholesterol was significantly associated with composite CVD outcomes after adjustments (T3 vs T1: hazard ratio [HR]; 1.07, 95% confidence interval [CI]: 1.04-1.10, p-trend<0.001). Remnant cholesterol was associated with myocardial infarction (T3 vs T1:HR: 1.20, 95% CI: 1.06-1.34, p-trend=0.002), angina pectoris (T3 vs T1:HR: 1.09, 95% CI: 1.05-1.14, p-trend<0.001), stroke (T3 vs T1:HR: 1.08, 95% CI: 1.02-1.14, p-trend=0.007), and HF (T3 vs T1:HR: 1.08, 95% CI: 1.04-1.12, p-trend<0.001), while we found a marginal inverse association between remnant cholesterol and AF (T3 vs T1:HR: 0.92, 95% CI: 0.86-1.00, p-trend=0.054)., Conclusion: Remnant cholesterol was positively associated with ASCVD and HF, while we found a marginal inverse association between remnant cholesterol and AF., (Copyright © 2023. Published by Elsevier Inc.)

Background: There is a paucity of data regarding shorter life expectancy after aortic valve replacement (AVR) in patients with severe aortic stenosis (AS)., Methods: Among 3815 patients with severe AS enrolled in the CURRENT AS (Contemporary outcomes after sURgery and medical tREatmeNT in patients with severe Aortic Stenosis) registry, there were 1469 patients (initial AVR: n = 647; conservative strategy: n = 822) with low surgical risk, 1642 patients (initial AVR: n = 433; conservative strategy: n = 1209) with intermediate surgical risk, and 704 patients (initial AVR: n = 117; conservative strategy: n = 587) with high surgical risk. Among 1163 patients who actually underwent surgical AVR as the initial strategy, patients were divided into 4 groups according to age <65 years (n = 185), 65 to 74 (n = 394), 75 to 80 (n = 345), and >80 (n = 239). The expected survival of the general Japanese population was obtained from the Statistics Bureau of Japan. The surgical risk was estimated using The Society of Thoracic Surgery (STS) score., Results: The median follow-up was 3.7 years. The cumulative incidences of all-cause death were significantly lower in the initial AVR strategy than in the initial conservative strategy across the 3 STS groups. Shorter life expectancy after surgical AVR was seen especially in younger patients. The observed mortality in low-risk patients was comparable to the expected mortality across all the age-groups, while intermediate-risk patients aged <75 years, and high-risk patients across all age-groups had higher mortality compared with the expected mortality., Conclusions: The risk stratification according to age and STS score might be useful to estimate shorter life expectancy after AVR, and these findings have implications for decision making in the choice of surgical or transcatheter AVR., (Copyright © 2023 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: The studies evaluating patients' characteristics and lipid-lowering therapy for patients with homozygous familial hypercholesterolemia (HoFH) are scarce., Objectives: This study aims to evaluate the characteristics of and treatments for patients with HoFH., Methods: This study included 201 patients who were diagnosed with definite or probable HoFH from the National Database of the Japanese Ministry of Health, Labour, and Welfare., Results: The patients' median age at diagnosis was 27 years and exhibited a bimodal distribution. Approximately 70% of patients had coronary artery disease. Regarding genetic backgrounds, mutations in the low-density lipoprotein (LDL) receptor ( LDLR ) were identified in most of the patients, followed by proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) and double heterozygotes of LDLR . High-intensity statins were introduced to 74% of the patients, lipoprotein apheresis was performed in 21%, and PCSK9 inhibitors were administered to 50%. The mean of LDL cholesterol before and after treatment were 10.1 mmol/L and 3.9 mmol/L, respectively. Patients with coronary artery disease had significantly decreased LDL cholesterol. A quarter of the patients (n = 49, 24%) exhibited valvular diseases, particularly aortic valvular disease (n = 34, 61%)., Conclusions: The national epidemiological study of patients with HoFH showed patient's clinical and genetic characteristics and LDL-lowering therapy in Japan. There was considerable diversity in the severity of phenotypes, including LDL cholesterol levels, among patients with HoFH. In Japan, the management of LDL cholesterol in HoFH is still inadequate despite the availability of intensive lipid-lowering therapies., Competing Interests: This work is supported by a grant from the Labor and Welfare Sciences Research Grant for Research on Rare and Intractable Diseases (21FC0201). The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

It is important to clarify the precise impact of mitral regurgitation (MR) on long-term outcomes in acute myocardial infarction (AMI) patients who underwent percutaneous coronary intervention (PCI). In the Coronary Revascularization Demonstrating Outcome study in Kyoto Acute Myocardial Infarction (CREDO-Kyoto AMI) Registry Wave-2, the study population consisted of 5,266 patients with AMI who underwent PCI. The clinical outcomes of all-cause death, cardiovascular death, and hospitalization for heart failure (HF) were compared according to the severity of MR. Mild and moderate/severe MR were identified in 2,112 (40%) and 531 patients (10%), respectively. Patients with greater severity of MR were more likely to be old, had more co-morbidities, and more often presented with large myocardial infarction with HF. During median follow-up duration of 5.6 (interquartile range: 4.2 to 6.6) years, as the MR severity increased from no, mild, to moderate/severe MR, the cumulative 5-year incidences of all-cause death, cardiovascular death and hospitalization for HF incrementally increased ([15.3%, 19.6%, 33.3%], [8.9%, 11.7%, 21.0%] and [5.9%, 12.4%, 23.9%], respectively, P for all<0.001). After adjusting for confounders, however, mild and moderate/severe MR were not independently associated with the higher risks for all-cause death (hazard ratio [95% confidence interval]:1.05 [0.92 to 1.19], p = 0.51, and 1.10 [0.92 to 1.32], p = 0.28) and cardiovascular death (1.01 [0.85 to 1.21], p = 0.89, and 0.93 [0.73 to 1.18], p = 0.54) as compared with no MR. Both mild and moderate/severe MR were independently associated with the higher risks for hospitalization for HF (1.73 [1.42 to 2.11], p <0.001, and 2.23 [1.73 to 2.87], p <0.001). In a large population of patients with AMI who underwent PCI, MR was not independently associated with higher long-term mortality risk but was independently associated with higher risk for hospitalization for HF., Competing Interests: Declaration of Competing Interest Dr. Shiomi reports personal fees from Boston Scientific, personal fees from Abbot Vascular, and personal fees from Daiichi Sankyo. Dr. Morimoto reports lecturer's fees from AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Japan Lifeline, Kowa, Toray and Tsumura; manuscript fees from Bristol-Myers Squibb and Kowa; advisory board for Novartis and Teijin. Dr. Tamura reports personal fees from Daiichi Sankyo and personal fees from Bayer. Dr. Furukawa reports personal fees from Daiichi Sankyo, personal fees from Bayer, personal fees from Bristol-Myers Squibb, personal fees from Pfizer, and personal fees from Boehringer Ingelheim. Dr. Nakagawa reports modest research grant from Abbott Vascular and Boston Scientific, and modest honoraria from Abbott Vascular, Bayer, and Boston Scientific. Dr. Kimura reports significant honoraria from Abbott Vascular, and modest honoraria from Astellas, AstraZeneca, Bayer, Boston Scientific, Kowa, and Sanofi. The remaining authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: There is a scarcity of studies comparing the clinical outcomes after percutaneous coronary intervention (PCI) for women and men stratified by the presentation of acute coronary syndromes (ACS) or stable coronary artery disease (CAD)., Methods and results: The study population included 26,316 patients who underwent PCI (ACS: n=11,119, stable CAD: n=15,197) from the CREDO-Kyoto PCI/CABG registry Cohort-2 and Cohort-3. The primary outcome was all-cause death. Among patients with ACS, women as compared with men were much older. Among patients with stable CAD, women were also older than men, but with smaller difference. The cumulative 5-year incidence of all-cause death was significantly higher in women than in men in the ACS group (26.2% and 17.9%, log rank P<0.001). In contrast, it was significantly lower in women than in men in the stable CAD group (14.2% and 15.8%, log rank P=0.005). After adjusting confounders, women as compared with men were associated with significantly lower long-term mortality risk with stable CAD but not with ACS (hazard ratio [HR]: 0.75, 95% confidence interval [CI]: 0.69-0.82, P<0.001, and HR: 0.92, 95% CI: 0.84-1.01, P=0.07, respectively). There was a significant interaction between the clinical presentation and the mortality risk of women relative to men (interaction P=0.002)., Conclusions: Compared with men, women had significantly lower adjusted mortality risk after PCI among patients with stable CAD, but not among those with ACS.

Background: There is scarce data evaluating the current practice pattern and clinical outcomes for patients with severe aortic stenosis (AS), including both those who underwent surgical aortic valve replacement (SAVR) or transcatheter aortic valve implantation (TAVI) and those who were managed conservatively in the TAVI era., Methods and results: The Contemporary outcomes after sURgery and medical tREatmeNT in patients with severe Aortic Stenosis (CURRENT AS) Registry-2 is a prospective, physician-initiated, multicenter registry enrolling consecutive patients who were diagnosed with severe AS between April 2018 and December 2020 among 21 centers in Japan. The rationale for the prospective enrollment was to standardize the assessment of symptomatic status, echocardiographic evaluation, and other recommended diagnostic examinations such as computed tomography and measurement of B-type natriuretic peptide. Moreover, the schedule of clinical and echocardiographic follow up was prospectively defined and strongly recommended for patients who were managed conservatively. The entire study population consisted of 3,394 patients (mean age: 81.6 years and women: 60%). Etiology of AS was degenerative in 90% of patients. AS-related symptoms were present in 60% of patients; these were most often heart failure symptoms. The prevalence of high- and low-gradient AS was 58% and 42%, respectively, with classical and paradoxical low-flow low-gradient AS in 4.6% and 6.7%, respectively., Conclusions: The CURRENT AS Registry-2 might be large and meticulous enough to determine the appropriate timing of intervention for patients with severe AS in contemporary clinical practice.

The clinical significance of the CHADS 2 score remains unclear in patients with coronary artery disease (CAD) without atrial fibrillation (AF). Therefore, the purpose of this study was to evaluate the association between the CHADS 2 score and the long-term risk of ischemic stroke and its severity in patients with CAD with and without AF. Using the CREDO (Coronary Revascularization Demonstrating Outcome study)-Kyoto Registry Cohort-3, the present study population consisted of 11,516 patients with CAD who underwent percutaneous coronary intervention without oral anticoagulants at discharge. We divided the patients into 2 groups according to the presence (n = 721) or absence (n = 10,795) of AF. As the CHADS 2 score increased from 0 or 1 to 6, the cumulative 5-year incidence of ischemic stroke incrementally increased from 2.1% to 17.1% in patients without AF and from 4.2% to 40.7% in patients with AF. The cumulative 5-year incidence of ischemic stroke in patients without AF and a CHADS 2 score of 2 were numerically comparable to that in patients with AF and a CHADS 2 score of 1 (3.4% and 3.7%). In the 423 patients who developed ischemic stroke, the modified Rankin Scale score was not significantly different between patients with and without AF (p for trend = 0.12). In patients with and without AF, the increase in the CHADS 2 score was significantly associated with the greater prevalence of higher modified Rankin Scale scores (p for trend = 0.03 and <0.001, respectively). An increasing CHADS 2 score was associated with an incrementally increased risk for ischemic stroke and greater severity of ischemic stroke in patients with and without AF., Competing Interests: Disclosures Dr. Shiomi reports personal fees from Boston Scientific, Abbot Vascular, and Daiichi Sankyo. Dr. Morimoto reports modest honoraria from Bayer and Kowa and modest expert witness from Boston Scientific and Sanofi. Dr. Tamura reports personal fees from Daiichi Sankyo and Bayer. Dr. Furukawa reports personal fees from Daiichi Sankyo, Bayer, Bristol Myers Squibb, Pfizer, and Boehringer Ingelheim. Dr. Nakagawa reports a modest research grant from Abbott Vascular and Boston Scientific and modest honoraria from Abbott Vascular, Bayer, and Boston Scientific. Dr. Kimura reports significant honoraria from Abbott Vascular and modest honoraria from Astellas, AstraZeneca, Bayer, Boston Scientific, Kowa, and Sanofi. The remaining authors have no conflicts of interest to declare., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Aims: There is a scarcity of studies comparing percutaneous coronary intervention (PCI) using new-generation drug-eluting stents (DES) with coronary artery bypass grafting (CABG) in patients with multi-vessel coronary artery disease., Methods and Results: The CREDO-Kyoto PCI/CABG registry Cohort-3 enrolled 14927 consecutive patients who underwent first coronary revascularization with PCI or isolated CABG between January 2011 and December 2013. The current study population consisted of 2464 patients who underwent multi-vessel coronary revascularization including revascularization of left anterior descending coronary artery (LAD) either with PCI using new-generation DES (N = 1565), or with CABG (N = 899). Patients in the PCI group were older and more often had severe frailty, but had less complex coronary anatomy, and less complete revascularization than those in the CABG group. Cumulative 5-year incidence of a composite of all-cause death, myocardial infarction or stroke was not significantly different between the 2 groups (25.0% versus 21.5%, P = 0.15). However, after adjusting confounders, the excess risk of PCI relative to CABG turned to be significant for the composite endpoint (HR 1.27, 95%CI 1.04-1.55, P = 0.02). PCI as compared with CABG was associated with comparable adjusted risk for all-cause death (HR 1.22, 95%CI 0.96-1.55, P = 0.11), and stroke (HR 1.17, 95%CI 0.79-1.73, P = 0.44), but with excess adjusted risk for myocardial infarction (HR 1.58, 95%CI 1.05-2.39, P = 0.03), and any coronary revascularization (HR 2.66, 95%CI 2.06-3.43, P<0.0001)., Conclusions: In this observational study, PCI with new-generation DES as compared with CABG was associated with excess long-term risk for major cardiovascular events in patients who underwent multi-vessel coronary revascularization including LAD., Competing Interests: The authors have declared that no competing interests exist.

Background: Diabetes is a well-known risk factor for adverse outcomes after coronary revascularization., Objectives: This study sought to determine high-risk subgroups in whom the excess risks of diabetes relative to nondiabetes are particularly prominent and thus may benefit from more aggressive interventions., Methods: The study population consisted of 39,427 patients (diabetes: n = 15,561; nondiabetes: n = 23,866) who underwent first percutaneous coronary intervention (n = 33,144) or coronary artery bypass graft (n = 6,283) in the pooled CREDO-Kyoto PCI/CABG (Coronary Revascularization Demonstrating Outcome Study in Kyoto Percutaneous Coronary Intervention/Coronary Artery Bypass Graft) registry. The primary outcome measure was major adverse cardiovascular and cerebral endpoints (MACCE), which was defined as a composite of all-cause death, myocardial infarction, and stroke., Results: With median follow-up of 5.6 years, diabetes was associated with significantly higher adjusted risks for MACCE. The excess adjusted risks of diabetes relative to nondiabetes for MACCE increased with younger age (≤64 years: adjusted HR: 1.30; 95% CI: 1.19-1.41; P  < 0.001; 64-73 years: adjusted HR: 1.24; 95% CI: 1.16-1.33; P  < 0.001; >73 years: adjusted HR: 1.17; 95% CI: 1.10-1.23; P  < 0.001; P interaction  < 0.001), mainly driven by greater excess adjusted mortality risk of diabetes relative to nondiabetes in younger tertile. No significant interaction was observed between adjusted risk of diabetes relative to nondiabetes for MACCE and other subgroups such as sex, mode of revascularization, and clinical presentation of acute myocardial infarction., Conclusions: The excess risk of diabetes relative to nondiabetes for MACCE was profound in the younger population. This observation suggests more aggressive interventions for secondary prevention in patients with diabetes might be particularly relevant in younger patients., Competing Interests: This study was supported by an educational grant from the Research Institute for Production Development (Kyoto, Japan). Dr Yamaji has received a research grant from Abbott Vascular. Dr Shiomi has received honoraria from Abbott Vascular and Boston Scientific. Dr Morimoto has received lecturer's fees from Bristol-Myers Squibb, Daiichi Sankyo, Japan Lifeline, Kowa, Kyocera, Novartis, and Toray; manuscript fees from Bristol-Myers Squibb and Kowa; and has served on the Advisory Board of Sanofi. Dr Ehara has received honoraria from Abbott Vascular, Bayer, Boston Scientific, Medtronic, and Terumo. Dr Furukawa has received honoraria from Bayer, Kowa, and Sanofi. Dr Nakagawa has received research grants from Abbott Vascular and Boston Scientific; and honoraria from Abbott Vascular, Bayer, and Boston Scientific. Dr Kimura has received a research grant from Abbott Vascular; and honoraria from Astellas, AstraZeneca, Bayer, Boston Scientific, Kowa, and Sanofi. All the other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2022 The Authors.)

Recently, one observational study showed that patients with ST-segment elevation myocardial infarction (STEMI) without standard cardiovascular risk factors were associated with increased mortality compared with patients with risk factors. This unexpected result should be evaluated in other populations including those with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) and chronic coronary syndrome (CCS). Among 30,098 consecutive patients undergoing first coronary revascularization in the CREDO-Kyoto PCI/CABG (Coronary Revascularization Demonstrating Outcome Study in Kyoto Percutaneous Coronary Intervention/Coronary Artery Bypass Grafting) registry cohort-2 and 3, we compared clinical characteristics and outcomes between patients with and without risk factors stratified by their presentation (STEMI n = 8,312, NSTE-ACS n = 3,386, and CCS n = 18,400). Patients with risk factors were defined as having at least one of the following risk factors: hypertension, dyslipidemia, diabetes, and current smoking. The proportion of patients without risk factors was low (STEMI: 369 patients [4.4%], NSTE-ACS: 110 patients [3.2%], and CCS: 462 patients [2.5%]). Patients without risk factors compared with those with risk factors more often had advanced age, low body weight, and malignancy and less often had history of atherosclerotic disease and prescription of optimal medical therapy. In patients with STEMI, patients without risk factors compared with those with risk factors were more often women and more often had atrial fibrillation, long door-to-balloon time, and severe hemodynamic compromise. During a median of 5.6 years follow-up, patients without risk factors compared with those with risk factors had higher crude incidence of all-cause death. After adjusting confounders, the mortality risk was significant in patients with CCS (hazard ratio [HR] 1.22, 95% confidence interval [CI] 1.01 to 1.49, p = 0.04) but not in patients with STEMI (HR 1.06, 95% CI 0.89 to 1.27, p = 0.52) and NSTE-ACS (HR 1.07, 95% CI, 0.74 to 1.54, p = 0.73). In conclusion, among patients undergoing coronary revascularization, patients without standard cardiovascular risk factors had higher crude incidence of all-cause death compared with those with at least one risk factor. After adjusting confounders, the mortality risk was significant in patients with CCS but not in patients with STEMI and NSTE-ACS., Competing Interests: Disclosures Dr. Morimoto receives lecturer's fees from Bayer, Daiichi Sankyo, Japan Lifeline, Kyocera, Mitsubishi Tanabe, Novartis, and Toray; the manuscript fees from Bristol-Myers Squibb and Kowa; and served advisory boards for Asahi Kasei, Boston Scientific, Bristol-Myers Squibb, and Sanofi. Dr. Shiomi receives personal fees from Abbott Vascular, Boston Scientific, and Daiichi Sankyo. Dr. Kato receives honoraria from AstraZeneca, Amgen, Bayer, Boehringer Ingelheim, Bristol-Meyers Squibb, Daiichi Sankyo, Merck Sharp & Dohme KK, Ono Pharmaceutical, Pfizer, Takeda, Tanabe-Mitsubishi; and research fund from Abbott Vascular, and Ono Pharmaceutical. Dr. Furukawa receives honoraria from Ono Pharmaceutical, Novartis, Daiichi Sankyo, Bayer, Otsuka Pharmaceutical, Kowa, Takeda, Sumitomo Dainippon Pharma, Pfizer, Bristol-Myers Squibb, and Sanofi. Dr. Nakagawa receives grant from Abbott Vascular and Boston Scientific, and personal fees from Abbott Vascular, Bayer, Boston Scientific, Bristol-Myers Squibb, and Daiichi Sankyo. Dr. Kimura receives personal fees from Abbott Vascular, Abiomed, Astellas, Astellas Amgen BioPharma, AstraZeneca, Bayer, Boston Scientific, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, Edwards Lifescience, Eisai, Daiichi Sankyo, Interscience, Japan Society for the Promotion of Science, Kowa, Kowa Pharmaceutical, Lifescience, Medical Review, Merck Sharp & Dohme, MSD Life Science Foundation, Mitsubishi Tanabe Pharma, Novartis Pharma, Ono Pharmaceutical, OrbusNeich, Otsuka Pharmaceutical, Pharmaceuticals and Medical Devices Agency, Philips, Public Health Research Foundation, Sanofi, Sumitomo Dainippon Pharma, Takeda Pharmaceutical, Terumo, Toray, and Tsumura. The remaining authors have no conflicts of interest to declare., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: There are limited data on the long-term stent-related adverse events as related to the duration of dual antiplatelet therapy (DAPT) in second-generation (G2) drug-eluting stents (DES) compared with first-generation (G1) DES., Objectives: This study sought to compare the long-term stent-related outcomes of G2-DES with those of G1-DES., Methods: The study group consisted of 15,009 patients who underwent their first coronary revascularization with DES from the CREDO-Kyoto PCI/CABG (Coronary Revascularization Demonstrating Outcome Study in Kyoto Percutaneous Coronary Intervention/Coronary Artery Bypass Grafting) Registry Cohort-2 (first-generation drug-eluting stent [G1-DES] period; n = 5,382) and Cohort-3 (second-generation drug eluting stent [G2-DES] period; n = 9,627). The primary outcome measures were definite stent thrombosis (ST) and target vessel revascularization (TVR)., Results: The cumulative 5-year incidences of definite ST and TVR were significantly lower in the G2-DES group than in the G1-DES group (0.7% vs 1.4%; P  < 0.001; and 16.2% vs 22.1%; P  < 0.001, respectively). The lower adjusted risk of G2-DES relative to G1-DES for definite ST and TVR remained significant (HR: 0.53; 95% CI: 0.37-0.76; P  < 0.001; and HR: 0.74; 95% CI: 0.68-0.81; P  < 0.001, respectively). In the landmark analysis that was based on the DAPT status at 1 year, the lower adjusted risk of on-DAPT status relative to off-DAPT was significant for definite ST beyond 1 year in the G1-DES stratum (HR: 0.42; 95% CI: 0.24-0.76; P  = 0.004) but not in the G2-DES stratum (HR: 0.66; 95% CI: 0.26-1.68; P  = 0.38) ( P interaction  = 0.14)., Conclusions: G2-DES compared with G1-DES were associated with a significantly lower risk for stent-related adverse events, including definite ST and TVR. DAPT beyond 1 year was associated with a significantly lower risk for very late ST of G1-DES but not for that of G2-DES., Competing Interests: This study was supported by an educational grant from the Research Institute for Production Development (Kyoto, Japan). Dr Shiomi has received honoraria from Abbott Vascular and Boston Scientific. Dr Morimoto has received lecturer fees from Bristol-Myers Squibb, Daiichi Sankyo, Japan Lifeline, Kowa, Kyocera, Novartis, and Toray; has received manuscript fees from Bristol-Myers Squibb and Kowa; and has received membership on the advisory board for Sanofi. Dr Kato has received honoraria from Daiichi-Sankyo, Ono Pharmaceutical, AstraZeneca, Tanabe-Mitsubishi, Bayer, Pfizer, Bristol-Myers Squibb, Boehringer Ingelheim, Takeda, MSD KK, and Amgen; and has received research funding from Ono Pharmaceutical and Abbott Japan. Dr Furukawa has received honoraria from Bayer, Kowa, and Sanofi. Dr Nakagawa has received research grants from Abbott Vascular and Boston Scientific; and has received honoraria from Abbott Vascular, Bayer, and Boston Scientific. Dr Kimura has received honoraria from Abbott Vascular, Astellas, AstraZeneca, Bayer, Boston Scientific, Kowa, and Sanofi. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2021 The Authors.)

Background: The detailed causes of death in non-ST-segment-elevation myocardial infarction (NSTEMI) have not been adequately evaluated compared to those in ST-segment elevation myocardial infarction (STEMI)., Methods: The study population was 6,228 AMI patients who underwent percutaneous coronary intervention (STEMI: 4,625 patients and NSTEMI: 1,603 patients). The primary outcome was all-cause death., Results: Within 6 months after AMI, the adjusted mortality risk was not significantly different between NSTEMI patients and STEMI patients (HR: 0.83, 95%CI: 0.67-1.03, P = 0.09). Regarding the causes of death within 6 months after AMI, mechanical complications more frequently occurred in STEMI patients than in NSTEMI patients, while proportions of post resuscitation status on arrival and heart failure were higher in in NSTEMI patients than in STEMI patients. Beyond 6 months after AMI, the adjusted mortality risk of NSTEMI relative to STEMI was not significantly different. (HR: 1.04, 95%CI: 0.90-1.20, P = 0.59). Regarding causes of death beyond 6 months after AMI, almost half of deaths were cardiovascular causes in both groups, and breakdown of causes of death was similar between NSTEMI and STEMI., Conclusion: The mortality risk within and beyond 6 months after AMI were not significantly different between STEMI patients and NSTEMI patients after adjusting confounders. Deaths due to post resuscitation status and heart failure were more frequent in NSTEMI within 6 months after AMI., Competing Interests: Dr. Shiomi reports modest honoraria from Abbott Vascular, and Boston Scientific. Dr. Morimoto reports modest honoraria from Bayer and Kowa, and modest expert witness from Boston Scientific and Sanofi. Dr. Kato reports modest honoraria from Daiichi-Sankyo, Ono Pharmaceutical, AstraZeneca, Tanabe-Mitsubishi, Bayer, Phizer, Bristol-Meyers Squibb, Boehringer ingelheim, Takeda, MSD KK, Amgen, and research fund from Ono Pharmaceutical and Abbott Japan. Dr. Ehara reports modest honoraria from Abbott Vascular, Bayer, Boston Scientific, Medtronic, and Terumo. Dr. Furukawa reports modest honoraria from Bayer, Kowa, and Sanofi. Dr. Nakagawa reports modest research grant from Abbott Vascular and Boston Scientific, and modest honoraria from Abbott Vascular, Bayer, and Boston Scientific. Dr. Kimura reports significant honoraria from Abbott Vascular, and modest honoraria from Astellas, AstraZeneca, Bayer, Boston Scientific, Kowa, and Sanofi. None of the article contents have not been published, nor under consideration for publication in any other journal before appearing in PLOS ONE.

Polypharmacy was reported to be associated with increased mortality in various populations. However, there is a scarcity of data on status of polypharmacy and association with long-term mortality in patients who underwent percutaneous coronary intervention (PCI). Among 12,291 patients who underwent first PCI in the CREDO-Kyoto PCI/CABG registry Cohort-3, we evaluated the number of medications at discharge from index PCI hospitalization, and compared long-term mortality across the 3 groups divided by the tertiles of the number of medications. The median number of medications was 6 (interquartile range: 5 to 8), and 88.0% of the patients were on >=5 medications. Most of medications were those related to cardiovascular disease. Patients taking more medications were older and more often had co-morbidities and guideline-indicated medications. The cumulative 5-year incidence of all-cause death increased incrementally with increasing number of medications (Tertile 1 [<=5]: 13.1%, Tertile 2 [6 to 7]: 13.9%, and Tertile 3 [>=8]: 18.0%, log-rank p <0.001). After adjusting confounders, the mortality risks of Tertile 2 and Tertile 3 relative to Tertile 1 were no longer significant (Tertile 2: hazard ratio 0.93; 95% confidence interval 0.84 to 1.04; p = 0.23, and Tertile 3: hazard ratio 0.91; 95% confidence interval 0.81 to 1.03; p = 0.14, respectively). In conclusion, in a real-world population of patients who underwent PCI, approximately 90% of patients were on >=5 medications. Increasing medications was associated with higher crude incidence of all-cause death, whereas adjusted mortality risks were similar regardless of the number of medications. These data might suggest that achievement of optimal medical therapy would be preferred, even if it might increase the number of medications used., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Data evaluating the effects of acute coronary syndrome (ACS) relative to stable coronary artery disease (CAD) on bleeding risk after percutaneous coronary intervention (PCI) are scarce., Methods and results: From the CREDO-Kyoto Registry Cohort-3, 13,258 patients undergoing first PCI (5,521 ACS; 7,737 stable CAD) were identified. Patients were further stratified according to ACS presentation and Academic Research Consortium High Bleeding Risk (HBR): ACS/HBR: n=2,502; ACS/no-HBR: n=3,019; stable CAD/HBR: n=3,905; and stable CAD/no-HBR: n=3,832. The primary bleeding endpoint was Bleeding Academic Research Consortium 3/5 bleeding, whereas the primary ischemic endpoint was myocardial infarction (MI)/ischemic stroke. Compared with stable CAD, ACS was associated with a significantly higher adjusted risk for bleeding (hazard ratio [HR] 1.85; 95% confidence interval [CI] 1.68-2.03; P<0.0001), with a markedly higher risk within 30 days (HR 4.24; 95% CI 3.56-5.06; P<0.0001). Compared with the stable CAD/no-HBR group, the ACS/HBR, no-ACS/HBR, and ACS/no-HBR groups were associated with significantly higher adjusted risks for bleeding, with HRs of 3.05 (95% CI 2.64-3.54; P<0.0001), 1.89 (95% CI 1.66-2.15; P<0.0001), and 1.69 (95% CI 1.45-1.98; P<0.0001), respectively. There was no excess adjusted risk of the ACS relative to stable CAD group for MI/ischemic stroke (HR 1.07; 95% CI 0.94-1.22; P=0.33)., Conclusions: Bleeding risk after PCI depended on both ACS presentation and HBR, with a significant effect of ACS within 30 days.

Background It remains controversial whether long-term clinical impact of newly diagnosed atrial fibrillation (AF) in the acute phase of acute myocardial infarction (AMI) is different from that of prior AF diagnosed before the onset of AMI. Methods and Results The current study population from the CREDO-Kyoto AMI (Coronary Revascularization Demonstrating Outcome Study in Kyoto Acute Myocardial Infarction) Registry Wave-2 consisted of 6228 patients with AMI who underwent percutaneous coronary intervention. The baseline characteristics and long-term clinical outcomes were compared according to AF status (newly diagnosed AF: N=489 [7.9%], prior AF: N=589 [9.5%], and no AF: N=5150 [82.7%]). Median follow-up duration was 5.5 years. Patients with newly diagnosed AF and prior AF had similar baseline characteristics with higher risk profile than those with no AF including older age and more comorbidities. The cumulative 5-year incidence of all-cause death was higher in newly diagnosed AF and prior AF than no AF (38.8%, 40.7%, and 18.7%, P <0.001). The adjusted hazard ratios (HRs) for mortality of newly diagnosed AF and prior AF relative to no AF remained significant with similar magnitude (HR, 1.31; 95% CI, 1.12-1.54; P <0.001, and HR, 1.32; 95% CI, 1.14-1.52; P <0.001, respectively). The cumulative 5-year incidence of stroke decreased in the order of newly diagnosed AF, prior AF and no AF (15.5%, 12.9%, and 6.3%, respectively, P <0.001). The higher adjusted HRs of both newly diagnosed AF and prior AF relative to no AF were significant for stroke, with a greater risk of newly diagnosed AF than that of prior AF (HR, 2.05; 95% CI, 1.56-2.69; P <0.001, and HR, 1.33; 95% CI, 1.00-1.78; P =0.048, respectively). The higher stroke risk of newly diagnosed AF compared with prior AF was largely driven by the greater risk within 30 days. The higher adjusted HRs of newly diagnosed AF and prior AF relative to no AF were significant for heart failure hospitalization (HR, 1.73; 95% CI, 1.35-2.22; P <0.001, and HR, 2.23; 95% CI, 1.82-2.74; P <0.001, respectively) and major bleeding (HR, 1.46; 95% CI, 1.23-1.73; P <0.001, and HR, 1.36; 95% CI, 1.15-1.60; P <0.001, respectively). Conclusions Newly diagnosed AF in AMI had risks for mortality, heart failure hospitalization, and major bleeding higher than no AF, and comparable to prior AF. The risk of newly diagnosed AF for stroke might be higher than that of prior AF.

Background Heart failure might be an important determinant in choosing coronary revascularization modalities. There was no previous study evaluating the effect of heart failure on long-term clinical outcomes after percutaneous coronary intervention (PCI) relative to coronary artery bypass grafting (CABG). Methods and Results Among 14 867 consecutive patients undergoing first coronary revascularization with PCI or isolated CABG between January 2011 and December 2013 in the CREDO-Kyoto PCI/CABG registry Cohort-3, we identified the current study population of 3380 patients with three-vessel or left main coronary artery disease, and compared clinical outcomes between PCI and CABG stratified by the subgroup based on the status of heart failure. There were 827 patients with heart failure (PCI: N=511, and CABG: N=316), and 2553 patients without heart failure (PCI: N=1619, and CABG: N=934). In patients with heart failure, the PCI group compared with the CABG group more often had advanced age, severe frailty, acute and severe heart failure, and elevated inflammatory markers. During a median 5.9 years of follow-up, there was a significant interaction between heart failure and the mortality risk of PCI relative to CABG (interaction P =0.009), with excess mortality risk of PCI relative to CABG in patients with heart failure (HR, 1.75; 95% CI, 1.28-2.42; P <0.001) and no excess mortality risk in patients without heart failure (HR, 1.04; 95% CI, 0.80-1.34; P =0.77). Conclusions There was a significant interaction between heart failure and the mortality risk of PCI relative to CABG with excess risk in patients with heart failure and neutral risk in patients without heart failure.

Objectives: To evaluate utility of the complex percutaneous coronary intervention (PCI) criteria in real-world practice., Background: Applicability of procedural complexity criteria for risk stratification has not been adequately evaluated in real-world practice., Methods: Among 13,087 patients undergoing first PCI in the CREDO-Kyoto registry cohort-2, the study population consisted of 7,871 patients after excluding patients with acute myocardial infarction and those without stent implantation. Complex PCI was defined as PCI, which fulfills at least one of the followings: three vessels treated, > = 3 stents implanted, > = 3 lesions treated, bifurcation with two stents, >60 mm total stent lengths, and target of chronic total occlusion., Results: The cumulative incidences of and adjusted risks for the primary ischemic (myocardial infarction/ischemic stroke), and bleeding (GUSTO moderate/severe) endpoints were significantly higher in patients with complex PCI (N = 2,777 [35%]) than in those with noncomplex PCI (N = 5,094 [65%]) (15.4% vs. 10.9%, log-rank p < .001; odds ratio (OR): 1.53, 95% confidence interval (CI): 1.31-1.79, p < .001, and 11.9% vs. 9.9%, log-rank p = .004; OR: 1.24, 95% CI: 1.05-1.46, p = .01). In the 30-day landmark analysis, the higher risks of patients with complex PCI for ischemic and major bleeding events were only seen within 30 days after PCI (ischemic; within 30 days: HR: 2.19, 95% CI: 1.79-2.69, p < .001; beyond 30 days: HR: 1.11, 95% CI: 0.92-1.34, p = .26, and bleeding; within 30 days: HR: 1.56, 95% CI: 1.13-2.16, p = .007; beyond 30 days: HR: 1.11, 95% CI: 0.94-1.31, p = .22)., Conclusions: Patients with complex PCI as compared with patients with noncomplex PCI had a higher risk for both ischemic and bleeding events mainly within 30 days after PCI., (© 2020 Wiley Periodicals LLC.)

Chronic kidney disease (CKD) might be an important determinant in choosing percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG). However, there is a scarcity of studies evaluating the effect of CKD on long-term outcomes after PCI relative to CABG in the population including severe CKD. Among 30257 consecutive patients patients who underwent first coronary revascularization with PCI or isolated CABG in the CREDO-Kyoto PCI/CABG registry Cohort-2 (n = 15330) and Cohort-3 (n = 14,927), we identified the current study population of 12,878 patients with multivessel or left main disease, and compared long-term clinical outcomes between PCI and CABG stratified by the subgroups based on the stages of CKD (no CKD: eGFR >=60 ml/min/1.73m 2 , moderate CKD: 60> eGFR >=30 ml/min/1.73m 2 , and severe CKD: eGFR <30 ml/min/1.73m 2 or dialysis). There were 6,999 patients without CKD (PCI: n = 5,268, and CABG: n = 1,731), 4,427 patients with moderate CKD (PCI: n = 3,226, and CABG: n = 1,201), and 1,452 patients with severe CKD (PCI: n = 989, and CABG: n = 463). During median 5.6 years of follow-up, the excess mortality risk of PCI relative to CABG was significant regardless of the stages of CKD without interaction (no CKD: HR, 1.36; 95%CI, 1.12 to 1.65; p = 0.002, moderate CKD: HR, 1.40; 95%CI, 1.17 to 1.67; p <0.001, and severe CKD: HR, 1.33; 95%CI, 1.09 to 1.62; p = 0.004, Interaction p = 0.83). There were no significant interactions between CKD and the effect of PCI relative to CABG for all the outcome measures evaluated. In conclusion, PCI compared with CABG was associated with significantly higher risk for all-cause death regardless of the stages of CKD without any significant interaction., Competing Interests: Disclosures Dr. Morimoto reports honoraria from Bayer and Kowa, and expert witness from Boston Scientific and Sanofi. Dr. Shiomi reports honoraria from Abbott Vascular, and Boston Scientific. Dr. Furukawa reports honoraria from Bayer, Kowa, and Sanofi. Dr. Nakagawa reports research grant from Abbott Vascular and Boston Scientific, and honoraria from Abbott Vascular, Bayer, and Boston Scientific. Dr. Kimura reports honoraria from Abbott Vascular, Astellas, AstraZeneca, Bayer, Boston Scientific, Kowa, and Sanofi., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Long-term safety of percutaneous coronary intervention (PCI) as compared with coronary artery bypass grafting (CABG) is still controversial in patients with unprotected left main coronary artery disease (ULMCAD), and there is a scarcity of real-world data on the comparative long-term clinical outcomes between PCI and CABG for ULMCAD in new-generation drug-eluting stents era. The CREDO-Kyoto PCI/CABG registry Cohort-3 enrolled 14927 consecutive patients undergoing first coronary revascularization with PCI or isolated CABG between January 2011 and December 2013, and we identified 855 patients with ULMCAD (PCI: N = 383 [45%], and CABG: N = 472 [55%]). The primary outcome measure was all-cause death. Median follow-up duration was 5.5 (interquartile range: 3.9 to 6.6) years. The cumulative 5-year incidence of all-cause death was not significantly different between the PCI and CABG groups (21.9% vs 17.6%, Log-rank p = 0.13). After adjusting confounders, the excess risk of PCI relative to CABG remained insignificant for all-cause death (HR, 1.00; 95% CI, 0.68 to 1.47; p = 0.99). There were significant excess risks of PCI relative to CABG for myocardial infarction and any coronary revascularization (HR, 2.07; 95% CI, 1.30 to 3.37; p = 0.002, and HR, 2.96; 95% CI, 1.96 to 4.46; p < 0.001), whereas there was no significant excess risk of PCI relative to CABG for stroke (HR, 0.85; 95% CI, 0.50 to 1.41; p = 0.52). In conclusion, there was no excess long-term mortality risk of PCI relative to CABG, while the excess risks of PCI relative to CABG were significant for myocardial infarction and any coronary revascularization in the present study population reflecting real-world clinical practice in Japan., Competing Interests: Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

There is a scarcity of data comparing long-term clinical outcomes between percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) in patients with three-vessel coronary artery disease (3VD) in the new-generation drug-eluting stents era. CREDO-Kyoto PCI/CABG registry Cohort-3 enrolled 14927 consecutive patients who had undergone first coronary revascularization with PCI or isolated CABG between January 2011 and December 2013. We identified 2525 patients with 3VD (PCI: n = 1747 [69%], and CABG: n = 778 [31%]). The primary outcome measure was all-cause death. Median follow-up duration was 5.7 (interquartile range: 4.4 to 6.6) years. The cumulative 5-year incidence of all-cause death was significantly higher in the PCI group than in the CABG group (19.8% vs 13.2%, log-rank p = 0.001). After adjusting confounders, the excess risk of PCI relative to CABG for all-cause death remained significant (HR, 1.45; 95% CI, 1.14 to 1.86; p = 0.003), which was mainly driven by the excess risk for non-cardiovascular death (HR, 1.88; 95% CI, 1.30 to 2.79; p = 0.001), while there was no excess risk for cardiovascular death between PCI and CABG (HR, 1.19; 95% CI, 0.87 to 1.64; p = 0.29). There was significant excess risk of PCI relative to CABG for myocardial infarction (HR, 1.77; 95% CI, 1.19 to 2.69; p = 0.006), whereas there was no excess risk of PCI relative to CABG for stroke (HR, 1.24; 95% CI, 0.83 to 1.88; p = 0.30). In conclusion, in the present study population reflecting real-world clinical practice in Japan, PCI compared with CABG was associated with significantly higher risk for all-cause death, while there was no excess risk for cardiovascular death between PCI and CABG., Competing Interests: Declaration of Interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this study., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: To evaluate changes in demographics, clinical practices and long-term clinical outcomes of patients with ST segment-elevation myocardial infarction (STEMI) before and beyond 2010., Design: Multicentre retrospective cohort study., Setting: The Coronary Revascularization Demonstrating Outcome Study in Kyoto (CREDO-Kyoto) AMI Registries Wave-1 (2005-2007, 26 centres) and Wave-2 (2011-2013, 22 centres)., Participants: 9001 patients with STEMI who underwent coronary revascularisation (Wave-1: 4278 patients, Wave-2: 4723 patients)., Primary and Secondary Outcome Measures: The primary outcome was all-cause death at 3 years. The secondary outcomes were cardiovascular death, cardiac death, sudden cardiac death, non-cardiovascular death, non-cardiac death, myocardial infarction, definite stent thrombosis, stroke, hospitalisation for heart failure, major bleeding, target vessel revascularisation, ischaemia-driven target vessel revascularisation, any coronary revascularisation and any ischaemia-driven coronary revascularisation., Results: Patients in Wave-2 were older, more often had comorbidities and more often presented with cardiogenic shock than those in Wave-1. Patients in Wave-2 had shorter onset-to-balloon time and door-to-balloon time, were more frequently implanted drug-eluting stents, and received guideline-directed medication than those in Wave-1. The cumulative 3-year incidence of all-cause death was not significantly different between Wave-1 and Wave-2 (15.5% and 15.7%, p=0.77). The adjusted risk of all-cause death in Wave-2 relative to Wave-1 was not significant at 3 years (HR 0.92, 95% CI 0.83 to 1.03, p=0.14), but lower beyond 30 days (HR 0.86, 95% CI 0.75 to 0.98, p=0.03). The adjusted risks of Wave-2 relative to Wave-1 were significantly lower for definite stent thrombosis (HR 0.59, 95% CI 0.43 to 0.81, p=0.001) and for any coronary revascularisation (HR 0.75, 95% CI 0.69 to 0.81, p<0.001), but higher for major bleeding (HR 1.34, 95% CI 1.20 to 1.51, p=0.005)., Conclusions: We could not demonstrate improvement in 3-year mortality risk from Wave-1 to Wave-2, but we found reduction in mortality risk beyond 30 days. We also found risk reduction for definite stent thrombosis and any coronary revascularisation, but an increase in the risk of major bleeding from Wave-1 to Wave-2., Competing Interests: Competing interests: All authors have completed the Unified Competing Interest form and declare the following: HSh reports personal fees from Abbott Vascular, Boston Scientific and Daiichi Sankyo. TM reports lecturer's fees from Bayer, Daiichi Sankyo, Japan Lifeline, Kyocera, Mitsubishi Tanabe, Novartis and Toray; the manuscript fees from Bristol-Myers Squibb and Kowa; serving on advisory boards for Asahi Kasei, Boston Scientific, Bristol-Myers Squibb and Sanofi. ETK reports grant from Ono Pharmaceutical and reports personal fees from Daiichi Sankyo, AstraZeneca, Bristol-Myers Squibb, Tanabe-Mitsubishi Pharma, Ono Pharmaceutical, MSD KK and Pfizer. NE reports personal fees from Abbott Vascular, Medtronic, Terumo, Bayer, Boston Scientific, Daiichi-Sankyo, Edwards Lifescience, Pfizer, Bristol Myers Squibb, Takeda and Boehringer Ingelheim. YF reports personal fees from Daiichi Sankyo, Bayer, Sanofi, Kowa, Pfizer, Bristol-Myers Squibb, Otsuka Parmaceutical, Sumitomo Dainippon Pharma, Takeda and Ono Pharmaceutical. YN reports grant from Abbott Vascular and Boston Scientific, and reports personal fees from Abbott Vascular, Bayer, Boston Scientific, Bristol-Myers Squibb, Daiichi Sankyo. TKi reports personal fees from Abbott Vascular, MSD, Eisai, Edwards Lifescience, Ono Pharmaceutical, Tsumura, Medical Review, Kowa, Sanofi, Daiichi Sankyo, Takeda Pharmaceutical, Pharmaceuticals and Medical Devices Agency, Abiomed, Bayer, Bristol-Myers Squibb, Boston Scientific, Lifescience, Toray, Astellas Amgen Biopharma, Astellas, AstraZeneca, Otsuka Parmaceutical, OrbusNeich, MSD Life Science Foundation, Public Health Research Foundation, Chugai Pharmaceutical, Boehringer Ingelheim, Japan Society for the Promotion of Science, Interscience, Philips, Kowa Pharmaceutical, Mitsubishi Tanabe Pharma, Terumo, Novartis Pharma and Sumitomo Dainippon Pharma., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

There is a scarcity of data on incidence, risk factors, especially clinical severity, and long-term prognostic impact of periprocedural stroke after coronary revascularization in contemporary real-world practice. Among 14,867 consecutive patients undergoing first coronary revascularization between January 2011 and December 2013 (percutaneous coronary intervention [PCI]: N = 13258, and coronary artery bypass grafting [CABG]: N = 1609) in the Coronary Revascularization Demonstrating Outcome Study in Kyoto PCI/CABG registry Cohort-3, we evaluated the details on periprocedural stroke. Periprocedural stroke was defined as stroke within 30 days after the index procedure. Incidence of periprocedural stroke was 0.96% after PCI and 2.13% after CABG (log-rank p <0.001). Proportions of major stroke defined by modified Rankin Scale ≥2 at hospital discharge were 68% after PCI, and 77% after CABG. Independent risk factors of periprocedural stroke were acute coronary syndrome (ACS), carotid artery disease, advanced age, heart failure, and end-stage renal disease after PCI, whereas they were ACS, carotid artery disease, atrial fibrillation, chronic obstructive pulmonary disease, malignancy, and frailty after CABG. There was excess long-term mortality risk of patients with periprocedural stroke relative to those without after both PCI and CABG (hazard ratio 1.71 [1.25 to 2.33], and hazard ratio 4.55 [2.79 to 7.43]). In conclusion, incidence of periprocedural stroke was not negligible not only after CABG, but also after PCI in contemporary real-world practice. Majority of patients with periprocedural stroke had at least mild disability at hospital discharge. ACS and carotid artery disease were independent strong risk factors of periprocedural stroke after both PCI and CABG. Periprocedural stroke was associated with significant long-term mortality risk after both PCI and CABG., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: To evaluate patient characteristics and long-term outcomes in patients with non-ST-segment elevation acute coronary syndrome (NSTEACS) in the past two decades., Design: Multicenter retrospective study., Setting: The Coronary REvascularization Demonstrating Outcome Study in Kyoto (CREDO-Kyoto) percutaneous coronary intervention (PCI)/coronary artery bypass grafting (CABG) Registry Cohort-2 (2005-2007) and Cohort-3 (2011-2013)., Participants: 3254 patients with NSTEACS who underwent first coronary revascularisation., Primary and Secondary Outcome Measures: The primary outcome was all-cause death. The secondary outcomes were cardiovascular death, cardiac death, sudden cardiac death, non-cardiovascular death, non-cardiac death, myocardial infarction, definite stent thrombosis, stroke, hospitalisation for heart failure, major bleeding, any coronary revascularisation and target vessel revascularisation., Results: Patients in Cohort-3 were older and more often had heart failure at admission than those in Cohort-2. The prevalence of PCI, emergency procedure and guideline-directed medical therapy was higher in Cohort-3 than in Cohort-2. In patients who received PCI, the prevalence of transradial approach, drug-eluting stent use and intravascular ultrasound use was higher in Cohort-3 than in Cohort-2. There was no change in 3-year adjusted mortality risk from Cohort-2 to Cohort-3 (HR 1.00, 95% CI 0.83 to 1.22, p=0.97). Patients in Cohort-3 compared with those in Cohort-2 were associated with lower adjusted risks for stroke (HR 0.65, 95% CI 0.46 to 0.92, p=0.02) and any coronary revascularisation (HR 0.76, 95%CI 0.66 to 0.87, p<0.001), but with higher risk for major bleeding (HR 1.25, 95% CI 1.06 to 1.47, p=0.008). The unadjusted risk for definite stent thrombosis was lower in Cohort-3 than in Cohort 2 (HR 0.29, 95% CI 0.11 to 0.67, p=0.003)., Conclusions: In the past two decades, we did not find improvement for mortality in patients with NSTEACS. We observed a reduction in the risks for definite stent thrombosis, stroke and any coronary revascularisation, but an increase in the risk for major bleeding., Competing Interests: Competing interests: HS reports personal fees from Abbott Vascular, Boston Scientific and Daiichi Sankyo. TM reports lecturer’s fees from Bayer, Daiichi Sankyo, Japan Lifeline, Kyocera, Mitsubishi Tanabe, Novartis and Toray; the manuscript fees from Bristol-Myers Squibb and Kowa; served advisory boards for Asahi Kasei, Boston Scientific, Bristol-Myers Squibb and Sanofi. NE reports personal fees from Abbott Vascular, Medtronic, Terumo, Bayer, Boston Scientific, Daiichi-Sankyo, Edwards Lifescience, Pfizer, Bristol Myers Squibb, Takeda and Boehringer Ingelheim. YF reports personal fees from Daiichi Sankyo, Bayer, Sanofi, Kowa, Pfizer, Bristol-Myers Squibb, Otsuka Parmaceutical, Sumitomo Dainippon Pharma, Takeda and Ono Pharmaceutical. YN reports grant from Abbott Vascular and Boston Scientific, and reports personal fees from Abbott Vascular, Bayer, Boston Scientific, Bristol-Myers Squibb, Daiichi Sankyo. TK reports personal fees from Abbott Vascular, MSD, Eisai, Edwards Lifescience, Ono Pharmaceutical, Tsumura, Medical Review, Kowa, Sanofi, Daiichi Sankyo, Takeda Pharmaceutical, Pharmaceuticals and Medical Devices Agency, Abiomed, Bayer, Bristol-Myers Squibb, Boston Scientific, Lifescience, Toray, Astellas Amgen Biopharma, Astellas, AstraZeneca, Otsuka Parmaceutical, OrbusNeich, MSD Life Science Foundation, Public Health Research Foundation, Chugai Pharmaceutical, Boehringer Ingelheim, Japan Society for the Promotion of Science, Interscience, Philips, Kowa Pharmaceutical, Mitsubishi Tanabe Pharma, Terumo, Novartis Pharma and Sumitomo Dainippon Pharma., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Two randomized control trials demonstrated that transcatheter aortic valve implantation was associated with 1-2 year clinical outcomes comparable or even superior to surgical aortic valve replacement (SAVR) in low surgical risk patients with severe aortic stenosis (AS). However, no previous study has reported the clinical outcomes after SAVR in Japanese patients with low surgical risk. From 3815 consecutive patients enrolled in the CURRENT AS registry, we retrieved 220 patients who underwent SAVR in reference to the inclusion and exclusion criteria of the PARTNER 3 trial. Age and surgical risk score in the current study population were comparable to those in the PARTNER 3 trial (Age: 75 years versus 74 years, and STS-PROM score: 2.3 versus 1.9). The cumulative incidence of a composite all-cause death or stroke was comparable between the current study population and the SAVR patients in the PARTNER 3 trial both at 30-day (2.3% versus 3.3%), and at 1-year (4.1% versus 4.9%). The clinical outcomes of SAVR in low surgical risk patients with severe AS selected from a real world Japanese registry according to the inclusion and exclusion criteria of the PARTNER 3 trial was favorable and numerically comparable to those of SAVR patients in the PARTNER 3 trial.

Background: Atrial fibrillation (AF) and renal failure coexist and interact. However, scarce data about association between renal function and clinical outcomes in patients undergoing catheter ablation for AF are available. We sought to evaluate long-term renal function and clinical outcomes after AF ablation., Methods: We enrolled 791 non-dialysis patients undergoing catheter ablation for AF, and evaluated the incidence of worsening renal function (WRF) after the procedure, defined as >30% decline in estimate glomerular filtration rate., Results: Mean follow-up duration was 5.1±2.5 years. Five hundreds and twenty-six patients (66.5%) were free from recurrent atrial arrhythmias without any antiarrhythmic drugs at the time of final follow-up. Cumulative incidence of WRF was 13.2% at 5-year after procedure, which was significantly higher in patients with recurrent AF compared to those without (21.6% versus 8.7%, P<0.001). In the multivariable analysis, recurrent AF was an independent risk factor for WRF (adjusted hazard ratio [HR] 1.89, 95% confidence interval 1.27-2.81, P = 0.002), along with congestive heart failure, diabetes, and eGFR <60 ml/min/1.73m2 at baseline. Patients with WRF had significantly higher 5-year incidences of all-cause death, cardiovascular death, heart failure hospitalization, ischemic stroke, and major bleeding compared to those without WRF. After adjustment of baseline differences in the multivariate Cox model, the excessive risks of WRF for all-cause death and heart failure hospitalization remained significant (adjusted HR 3.46, P = 0.002; adjusted HR 3.67, P<0.001)., Conclusions: In AF patients undergoing catheter ablation for AF, arrhythmia recurrence was associated with WRF during follow-up, which was a strong predictor of adverse clinical outcomes., Competing Interests: The authors declared that no competing interests exist.

Contemporary Outcomes after Surgery and Medical Treatment in Patients with Severe Aortic Stenosis (CURRENT AS) registry was a large Japanese multicentre retrospective registry of consecutive patients with severe aortic stenosis (AS) before introduction of transcatheter aortic valve implantation. We sought to overview the data from the CURRENT AS registry to discuss the three major contemporary issues related to clinical practice in patients with severe AS: (1) under-referral/underuse of surgical aortic valve replacement (SAVR) in symptomatic patients with severe AS, (2) management of asymptomatic patients with severe AS and (3) management of patients with low-gradient severe aortic stenosis (LG-AS). First, despite the dismal prognosis of symptomatic patients with severe AS, SAVR, including those performed during follow-up, was reported to be underused. In the CURRENT AS registry, overall 53% of symptomatic patients underwent aortic valve replacement (AVR) during follow-up. Second, we reported that compared with conservative strategy, initial AVR strategy was associated with lower risk of all-cause death and heart failure hospitalisation in asymptomatic patients with severe AS. Although current recommendations for AVR are mainly dependent on the patient symptoms, some patients may not complain of any symptom because of their sedentary lifestyle. We also reported several important objective factors associated with worse clinical outcomes in asymptomatic patients with severe AS for risk stratification. Finally, initial AVR strategy was associated with better long-term clinical outcomes than conservative strategy in both patients with high-gradient AS and patients with LG-AS. The favourable effect of initial AVR strategy was also seen in patients with LG-AS with left ventricular ejection fraction of ≥50%., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: There are no data comparing transcatheter aortic valve implantation (TAVI) with surgical aortic valve replacement (SAVR) outcomes in real clinical practice in Japan., Methods and results: We combined 2 independent registries, the K-TAVI Registry (a 6-center prospective registry of consecutive patients who underwent TAVI) and the CURRENT AS Registry (a large, 27-center registry of 3,815 consecutive patients with severe aortic stenosis [AS]). In the K-TAVI Registry, 338 patients underwent TAVI with SAPIEN XT balloon-expandable valves from October 2013 to January 2016, whereas in the CURRENT AS Registry 237 patients with severe AS underwent SAVR from January 2003 to December 2011. Propensity score matching was conducted, with final cohort comprising 306 patients. The cumulative 2-year incidence of all-cause death and heart failure (HF) hospitalization did not differ significantly between the TAVI and SAVR groups (13.7% vs. 12.4% [P=0.81] and 7.9% vs 3.9% [P=0.13], respectively). After adjusting for residual confounders, there were no significant differences between the TAVI and SAVR groups in the risk for all-cause death (hazard ratio [HR] 0.74; 95% confidence interval [CI] 0.35-1.58; P=0.43) or HF hospitalization (HR 1.27; 95% CI 0.40-4.59; P=0.69)., Conclusions: These findings from 2 independent Japanese registries suggest that the 2-year risk of all-cause mortality and HF does not differ significantly between TAVI and SAVR groups in real-world practice in Japan.

Background: The effect of diabetes mellitus (DM) status on the long-term risk for heart failure (HF) in patients undergoing coronary revascularization has not been adequately evaluated., Methods and results: In this study, 15,231 patients who underwent coronary revascularization in the CREDO-Kyoto Registry Cohort-2 were divided into 2 groups according to DM status (DM group: n=5,999; Non-DM group: n=9,232). The DM group was further divided into 2 groups according to insulin treatment (insulin-treated DM [ITDM]: n=1,353; non-insulin-treated DM [NITDM]: n=4,646). The primary outcome measure was HF hospitalization. The cumulative 5-year incidence of HF hospitalization was significantly higher in the DM than non-DM group (11.0% vs. 6.6%, respectively; log-rank P<0.0001), and in the ITDM than NITDM group (14.6% vs. 10.0%, respectively; log-rank P<0.0001). After adjusting for confounders, the increased risk of HF hospitalization with DM relative to non-DM remained significant (hazard ratio [HR] 1.47, 95% confidence interval [CI] 1.30-1.67, P<0.0001), whereas the risk associated with ITDM relative to NITDM was not significant (HR 1.17, 95% CI 0.96-1.43, P=0.12)., Conclusions: The adjusted long-term risk for HF hospitalization after coronary revascularization was significantly higher in DM than non-DM patients, regardless of revascularization strategy, but did not differ between ITDM and NITDM patients.

There is a paucity of studies exploring whether the ischemia-bleeding trade-off could be different according to the stages of renal dysfunction in patients with atrial fibrillation (AF) who underwent percutaneous coronary intervention (PCI). Among 19,598 patients in a pooled database from 3 Japanese PCI studies (CREDO-Kyoto Cohort-2, RESET, and NEXT), 1,547 patients had concomitant AF. Patients were divided into 4 groups according to their renal function (Creatinine clearance [CCr] >60 ml/min: n = 703, 60≥ CCr >30 ml/min: n = 627, CCr ≤30 ml/min: n = 126, Dialysis: n = 91). The cumulative 3-year incidences of both the primary ischemic (ischemic stroke/myocardial infarction) and bleeding (GUSTO moderate/severe) outcome increased incrementally with worsening renal function (11.4%, 12.6%, 16.8%, and 31.7%, p <0.001, and 7.5%, 14.9%, 26.3%, and 29.5%, p <0.001, respectively). Compared with CCr >60 ml/min group, the excess adjusted risk for the primary ischemic outcome was significant only in dialysis group (hazards ratio [HR] 2.15, 95% confidence interval [CI] 1.22 to 3.69, p = 0.009), but not in 60≥ CCr >30 ml/min and CCr ≤30 ml/min groups (HR 0.89, 95% CI 0.62 to 1.29, p = 0.54, and HR 0.94, 95% CI 0.49 to 1.69, p = 0.83, respectively), whereas the excess adjusted risk for the primary bleeding outcome was significant in all 3 groups of renal dysfunction (HR 1.66, 95% CI 1.13 to 2.45, p = 0.01, HR 2.70, 95% CI 1.58 to 4.61, p <0.001, and HR 3.26, 95% CI 1.85 to 5.75, p <0.001, respectively). In conclusion, in AF patients receiving PCI, the worsening renal function was strongly associated with the increasingly higher risk for bleeding events, whereas the excess risk for ischemic events was significant only in patients on dialysis., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Transcatheter aortic valve implantation (TAVI) is criticized by some as an expensive treatment in super-elder patients with limited life expectancy. However, there is a knowledge gap regarding the magnitude of clinical benefit provided by TAVI in comparison with conservative management in patients with severe aortic stenosis (AS) in real clinical practice, which would be important in the decision making for TAVI., Methods: We combined two independent registries, namely CURRENT AS and K-TAVI registries. CURRENT AS was a multicenter registry enrolling 3815 consecutive patients with severe AS irrespective to treatment modalities between January 2003 and December 2011. K-TAVI was a multicenter, prospective registry including 449 consecutive patients with severe AS, who underwent TAVI with SAPIEN XT balloon-expandable valves between October 2013 and June 2016. In these 2 registries, 449 patients received TAVI and 894 patients were managed with conservative strategy. We conducted propensity score matching and finally obtained a cohort of 556 patients (278 patients for each group) for the analysis. The primary outcome measures were all-cause death and heart failure (HF) hospitalization at 2-year., Results: The cumulative 2-year incidences of all-cause death and HF hospitalization were significantly lower in the TAVI group than in the conservative group (16.8% versus 36.6%, P<0.001, and 10.7% versus 37.2%, P<0.001). After adjusting the residual confounders, TAVI reduced the risks of all-cause death (HR, 0.46; 95%CI, 0.32-0.69; P = 0.0001) and HF hospitalizations (HR, 0.25; 95%CI, 0.16-0.40; P<0.0001) compared with conservative strategy. There was no difference in the cumulative incidence of non-cardiovascular death between the 2 groups., Conclusions: TAVI in the early Japanese experience was associated with striking risk reduction for all-cause death as well as HF hospitalization as compared with the historical cohort of patients with severe AS who were managed conservatively just before introduction of TAVI in Japan., Competing Interests: The authors have declared that no competing interests exist.

Objectives: The aim of this study was to compare 7-year outcomes between the first-generation sirolimus-eluting stent (SES) and the new-generation everolimus-eluting stent (EES) in a randomized clinical trial., Background: There is a scarcity of very long-term (beyond 5 years) data from clinical trials investigating whether new-generation drug-eluting stents have clear clinical advantages over first-generation drug-eluting stents., Methods: RESET (Randomized Evaluation of Sirolimus-Eluting Versus Everolimus-Eluting Stent Trial) is the largest randomized trial comparing EES with SES (NCT01035450). Among a total of 3,197 patients in the original RESET population from 100 centers, the present extended 7-year follow-up study was conducted in 2,667 patients from 75 centers after excluding those patients enrolled from centers that denied participation. Complete 7-year follow-up was achieved in 91.5% of patients., Results: The cumulative 7-year incidence of the primary efficacy endpoint of target lesion revascularization was not significantly different between EES and SES (10.2% vs. 11.7%; hazard ratio: 0.87; 95% confidence interval: 0.68 to 1.10; p = 0.24). The risk for the primary safety endpoint of death or myocardial infarction trended lower with EES than with SES (20.6% vs. 23.6%; hazard ratio: 0.85; 95% confidence interval: 0.72 to 1.005; p = 0.06). The cumulative 7-year incidence of definite stent thrombosis was very low and similar between EES and SES (0.9% vs. 1.0%; p = 0.82). The lower risk of EES relative to SES was significant for the composite secondary endpoint of target lesion failure (13.3% vs. 18.1%; hazard ratio: 0.72; 95% confidence interval: 0.59 to 0.88; p = 0.001)., Conclusions: During 7 years of follow-up, the risk for target lesion revascularization was not significantly different between the new-generation EES and the first-generation SES., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The predictive ability of patient frailty on clinical outcomes after revascularization in patients with critical limb ischemia remains largely unknown., Methods and Results: We enrolled 643 patients with critical limb ischemia treated with endovascular therapy (N=486) or bypass surgery (N=157) in January 2010 to January 2016, and prospectively assessed them using a 9-level clinical frailty scale (CFS). Patients were divided into 3 groups according to CFS levels: low (CFS level, 1-3; N=234), intermediate (CFS level, 4-6; N=196), and high (CFS level, 7-9; N=213) groups. Clinical follow-up rate was 95.8% at 2 years. In the low, intermediate, and high CFS groups, 2-year overall survival rates were 80.5%, 63.1%, and 49.3% ( P <0.001) and amputation-free survival rates were 77.9%, 60.5%, and 46.2% ( P <0.001), respectively. In multivariable analysis, higher frailty was independently associated with all-cause death (intermediate CFS group: adjusted hazard ratio, 1.64; 95% confidence interval, 1.12-2.42; P =0.01; high CFS group: adjusted hazard ratio, 2.22; 95% confidence interval, 1.52-3.23; P <0.001) and a composite of all-cause death and major amputation (intermediate CFS group: adjusted hazard ratio, 1.72; 95% confidence interval, 1.19-2.48; P =0.004; high CFS group: adjusted hazard ratio, 2.34; 95% confidence interval, 1.64-3.35; P <0.001). Frailty was also independently associated with overall survival and amputation-free survival in patients aged ≤75 and >75 years, those who underwent endovascular therapy or bypass surgery, and those with or without chronic renal failure, without significant interactions., Conclusions: Frailty was independently associated with 2-year overall survival and amputation-free survival in patients with critical limb ischemia treated with revascularization, irrespective of age, revascularization mode, and chronic renal failure status., (© 2018 American Heart Association, Inc.)